Deuterated compounds, compositions, and methods for treating cancers associated with ETBR activation

ABSTRACT

Disclosed herein are deuterated compounds, pharmaceutical compositions thereof, and methods for treating ETBR-related cancers. Also disclosed herein is a delivery system for the controlled, systemic release of at least one deuterated ETBR antagonist, optionally in conjunction with an additional anti-oncologic agent.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.62/616,729, filed Jan. 12, 2018, which is incorporated herein byreference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jan. 11, 2019, isnamed “55520704201_SL.txt” and is 751 bytes in size.

BRIEF SUMMARY

Disclosed herein are compounds. In some embodiments, a compound can be acompound of Formula (1):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,where: n can be an integer from 0-5; m can be an integer from 0-3; X canbe a positively charged counterion; R₁ and R₃ can be independently —H,-D, —CH₃, —CH₂D, —CHD₂, or —CD₃; R_(2a), R_(2b), R₄, R₅, and R₆ can beindependently —CH₃, —CH₂D, —CHD₂, or —CD₃; and at least one of R₁, R₂,or R₃ comprises deuterium. In some embodiments, m can be 0, n can be 0,and R_(2a) and R_(2b) can be —CH₂D. In some embodiments, a compound canbe a compound of Formula (2):

or a pharmaceutically acceptable salt thereof. In some embodiments, acompound can be a compound of Formula (3):

or a pharmaceutically acceptable salt thereof. In some embodiments, acompound can be a compound of Formula (4):

or a pharmaceutically acceptable salt thereof. In some embodiments, acompound can be a compound of Formula (5):

or a pharmaceutically acceptable salt thereof. In some embodiments, acompound can be a compound of Formula 6:

In some embodiments, n can be 0 or 1. In some embodiments, n can be 1,R₁ can be -D; and R_(2a) and R_(2b) can be —CH₃. In some embodiments, ncan be 0, R₁ can be —H; R_(2a) can be —CH₃ and R_(2b) can be —CH₂D. Insome embodiments, n can be 0, R₁ can be —H; R_(2a) can be —CH₂D andR_(2b) can be —CH₃. In some embodiments, n can be 0, R₁ can be —H; andR_(2a) and R_(2b) can be —CH₂D. In some embodiments, n can be 1, R₁ canbe -D; and R_(2a) and R_(2b) can be —CH₂D.

Also disclosed herein are compounds or pharmaceutically acceptable saltsthereof selected from the group consisting of:

Also disclosed herein are pharmaceutical composition that comprises acompound as described herein and a pharmaceutically acceptableexcipient, diluent, or carrier. In some embodiments, a pharmaceuticalcomposition comprises a pharmaceutically acceptable carrier. In someembodiments, a pharmaceutically acceptable carrier can be dimethylsulfoxide (DMSO). In some embodiments, the compound is:

Also disclosed herein are methods of treating cancer that comprisesadministering to a subject in need thereof a pharmaceutical compositionas described herein. In some embodiments, a method can further compriseadministering an immune checkpoint inhibitor to the subject. In someembodiments, an immune checkpoint inhibitor can be an anti-PD1 antibody.

Also disclosed herein are methods of treating cancer in a subject inneed thereof, that comprises administering to the subject a compound asdescribed herein, wherein the compound can be in an amount effective fortreating or ameliorating at least one symptom of the cancer in thesubject. In some embodiments, a method can further compriseadministering to the subject at least one immune checkpoint inhibitor tothe subject. In some embodiments, the at least one immune checkpointinhibitor comprises at least one anti-PD1 antibody, at least oneanti-PD-L1 antibody, at least one anti-CTLA4 antibody, or anycombination thereof. In some embodiments, the at least one anti-PD1antibody comprises pidilizumab, BMS-936559, nivolumab, pembrolizumab orany combination thereof. In some embodiments, the at least oneanti-PD-L1 antibody compries atezolizumab, avelumab, durvalumab,MDX-1105, or any combination thereof. In some embodiments, the cancercan be a solid tumor cancer, malignant melanoma, metastatic melanoma,malignant squamous cell carcinoma, metastatic squamous cell carcinoma,glioblastoma, brain cancer, pancreatic cancer, colon cancer, breastcancer, ovarian cancer, prostate cancer, or any combination thereof. Insome embodiments, the compound and the immune checkpoint inhibitor canbe administered at different times. In some embodiments, the compoundcan be administered 2, 3, 4, or 5 times frequently as the immunecheckpoint inhibitor. In some embodiments, the compound can beadministered 3 times frequently as the immune checkpoint inhibitor. Insome embodiments, the compound can be administered 3 times every 2-3weeks and the immune checkpoint inhibitor can be administered 1 time theevery 2-3 weeks. In some embodiments, the compound can be administered 3times about every 21 days and the immune checkpoint inhibitor can beadministered 1 time the about every 21 days. In some embodiments, thesubject can be a human. In some embodiments, the subject can beresistant to an immunotherapy before the treatment. In some embodiments,the administration results in at least one of improved biologicactivity, increased stability, prolonged serum bioavailability,prolonged ETBR target engagement, or any combination thereof, comparedto a non-deuterated parent compound, as determined by measuring a serumET-1 level. In some embodiments, the administration restores TumorInfiltrating Lymphocytes (TILs), intratumoral tertiary lymphoid organ(TLO) formation, or a combination thereof, in a tumor microenvironment.

Also disclosed herein are methods of forming a tertiary lymphoid organ(TLO) within a tumor in a subject in need thereof, that comprisesadministering to the subject a compound as described herein, whereby thetumor can be reduced or eradicated. In some embodiments, the compound is

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound can be in a pharmaceuticallyacceptable excipient that comprises dimethyl sulfoxide (DMSO).

Also disclosed herein are compounds of Formula (7):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,where: R¹, R², R³, R⁴, or R⁵ can be independently hydrogen, halogen,hydroxyl, deuterium, halogen, hydroxy, amino, nitro, optionallysubstituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl,optionally substituted C₂-C₈ alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₁-C₈ alkoxy, optionally substitutedC₁-C₈ haloalkykl, optionally substituted aryl, or optionally substitutedheteroaryl, optionally wherein one or more of the carbons in thepiperidinyl ring can be a heteroatom selected from O, N, or S, orwherein the piperidinyl ring may contain one or more double bonds; R⁶can be optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₅-cycloalkyl, optionally substituted C₁-C₈ alkoxy, optionallysubstituted C₁-C₈ haloalkykl, optionally substituted aryl, or optionallysubstituted heteroaryl, wherein R⁶ optionally comprises deuterium; R⁷can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted polycyclic ring system, optionallysubstituted bicyclic, optionally substituted heterobycyclic, wherein R⁷optionally comprises deuterium; R⁸ and R⁹ can be independentlyoptionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₁-C₈ alkoxy, optionallysubstituted C₁-C₈ haloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, or —COOR′, or R⁸ and R⁹ may be taken together toform a optionally substituted cycloalkyl, optionally substitutedcycloalkyl heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, or optionally substituted polycyclic ringsystem, wherein R⁸ or R⁹ each optionally comprises deuterium; R′ can behydrogen, hydroxy, or C₁-C₈ alkyl; and wherein at least one of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, or R⁹ comprises deuterium. In some embodiments,two of R¹, R², R³, R⁴, or R⁵ comprise deuterium. Also disclosed hereinare pharmaceutical compositions that comprise an effective amount of thecompound, and a pharmaceutically acceptable carrier. In someembodiments, the pharmaceutically acceptable carrier can be dimethylsulfoxide (DMSO). Also disclosed herein are methods of treating cancerin a subject in need thereof, that comprises administering to thesubject the compound the pharmaceutical composition, wherein the methodcan be effective in treating or ameliorating at least one symptom of thecancer in the subject. In some embodiments, the method can furthercomprise administering to the subject at least one additionalanti-oncologic therapeutic agent. In some embodiments, the at least oneadditional anti-oncologic agent comprises a bRAF inhibitor, an immunecheckpoint inhibitor, a caspase-8 inhibitor, an ETAR antagonist,niacinamide, a chemotherapeutic agent, or any combination thereof. Insome embodiments, the at least one additional anti-oncologic agentcomprises at least one of the immune checkpoint inhibitor. In someembodiments, the at least one immune checkpoint inhibitor comprises atleast one anti-PD1 antibody, at least one anti-PD-L1 antibody, at leastone anti-CTLA4 antibody, or any combination thereof. In someembodiments, the at least one anti-PD1 antibody comprises pidilizumab,BMS-936559, nivolumab, pembrolizumab or any combination thereof. In someembodiments, the at least one anti-PD-L1 antibody compries atezolizumab,avelumab, durvalumab, MDX-1105, or any combination thereof. In someembodiments, the cancer can be a solid tumor cancer, malignant melanoma,metastatic melanoma, malignant squamous cell carcinoma, metastaticsquamous cell carcinoma, glioblastoma, brain cancer, pancreatic cancer,colon cancer, breast cancer, ovarian cancer, prostate cancer, or anycombination thereof. In some embodiments, the compound and the at leastone additional anti-oncologic agent can be administered at differenttimes. In some embodiments, the compound can be administered 2, 3, 4, or5 times frequently as the immune checkpoint inhibitor. In someembodiments, the compound can be administered 3 times frequently as theimmune checkpoint inhibitor. In some embodiments, the compound can beadministered 3 times every 2-3 weeks and the immune checkpoint inhibitorcan be administered 1 time the every 2-3 weeks. In some embodiments, thecompound can be administered 3 times about every 21 days and the immunecheckpoint inhibitor can be administered 1 time the about every 21 days.In some embodiments, the subject can be a human. In some embodiments,the subject can be resistant to an immunotherapy before the treatment.In some embodiments, the administration results in at least one ofimproved biologic activity, increased stability, prolonged serumbioavailability, prolonged ETBR target engagement, or any combinationthereof, compared to a non-deuterated parent compound, as determined bymeasuring a serum ET-1 level. In some embodiments, the administrationrestores Tumor Infiltrating Lymphocytes (TILs), intratumoral tertiarylymphoid organ (TLO) formation, or a combination thereof, in a tumormicroenvironment.

Also disclosed herein are compounds of Formula (8):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,where: R², R³, or R⁴ can be independently hydrogen, deuterium, halogen,hydroxy, amino, nitro, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkykl, aryl, or heteroaryl; R⁶ canbe C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₁-C₈alkoxy, C₁-C₈ haloalkykl, aryl, or heteroaryl, wherein R⁶ optionallycomprises deuterium; R⁷ can be substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, or asubstituted or unsubstituted polycyclic ring system, wherein R⁷optionally comprises deuterium; R⁸ and R⁹ can be independently C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈-cycloalkyl, C₁-C₈ alkoxy,C₁-C₈ haloalkykl, aryl, heteroaryl, or —COOR′, or R⁸ and R⁹ may be takentogether to form a substituted or unsubstituted cycloalkyl, substitutedor unsubstituted cycloalkyl heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, orsubstituted or unsubstituted polycyclic ring system, wherein R⁸ or R⁹each optionally comprises deuterium; R′ can be hydrogen, hydroxy, orC₁-C₈ alkyl; and wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,or R⁹ comprises deuterium. In some embodiments, two of R¹, R², R³, R⁴,or R⁵ comprise deuterium. Also disclosed herein are pharmaceuticalcompositions that comprise an effective amount of the compound, and apharmaceutically acceptable carrier. In some embodiments, thepharmaceutically acceptable carrier can be dimethyl sulfoxide (DMSO).Also disclosed herein are methods of treating cancer in a subject inneed thereof, that comprises administering to the subject the compoundthe pharmaceutical composition, wherein the method can be effective intreating or ameliorating at least one symptom of the cancer in thesubject. In some embodiments, the method can further compriseadministering to the subject at least one additional anti-oncologictherapeutic agent. In some embodiments, the at least one additionalanti-oncologic agent comprises a bRAF inhibitor, an immune checkpointinhibitor, a caspase-8 inhibitor, an ETAR antagonist, niacinamide, achemotherapeutic agent, or any combination thereof. In some embodiments,the at least one additional anti-oncologic agent comprises at least oneof the immune checkpoint inhibitor. In some embodiments, the at leastone immune checkpoint inhibitor comprises at least one anti-PD1antibody, at least one anti-PD-L1 antibody, at least one anti-CTLA4antibody, or any combination thereof. In some embodiments, the at leastone anti-PD1 antibody comprises pidilizumab, BMS-936559, nivolumab,pembrolizumab or any combination thereof. In some embodiments, the atleast one anti-PD-L1 antibody compries atezolizumab, avelumab,durvalumab, MDX-1105, or any combination thereof. In some embodiments,the cancer can be a solid tumor cancer, malignant melanoma, metastaticmelanoma, malignant squamous cell carcinoma, metastatic squamous cellcarcinoma, glioblastoma, brain cancer, pancreatic cancer, colon cancer,breast cancer, ovarian cancer, prostate cancer, or any combinationthereof. In some embodiments, the compound and the at least oneadditional anti-oncologic agent can be administered at different times.In some embodiments, the compound can be administered 2, 3, 4, or 5times frequently as the immune checkpoint inhibitor. In someembodiments, the compound can be administered 3 times frequently as theimmune checkpoint inhibitor. In some embodiments, the compound can beadministered 3 times every 2-3 weeks and the immune checkpoint inhibitorcan be administered 1 time the every 2-3 weeks. In some embodiments, thecompound can be administered 3 times about every 21 days and the immunecheckpoint inhibitor can be administered 1 time the about every 21 days.In some embodiments, the subject can be a human. In some embodiments,the subject can be resistant to an immunotherapy before the treatment.In some embodiments, the administration results in at least one ofimproved biologic activity, increased stability, prolonged serumbioavailability, prolonged ETBR target engagement, or any combinationthereof, compared to a non-deuterated parent compound, as determined bymeasuring a serum ET-1 level. In some embodiments, the administrationrestores Tumor Infiltrating Lymphocytes (TILs), intratumoral tertiarylymphoid organ (TLO) formation, or a combination thereof, in a tumormicroenvironment.

Also disclosed herein are compounds of Formula (9):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,where: R¹ R², R³, R⁴, or R⁵ can be independently hydrogen, deuterium,halogen, hydroxy, amino, nitro, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkyl, aryl, orheteroaryl; R⁶ can be C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₃-C₈-cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkykl, aryl, or heteroaryl,wherein R⁶ optionally comprises deuterium; R⁸ and R⁹ can beindependently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, R⁸ and R⁹ can be independently C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, C₃-C₈-cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkykl, aryl,heteroaryl, or —COOR′, or R⁸ and R⁹ may be taken together to form asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkyl heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedpolycyclic ring system, wherein R⁸ or R⁹ each optionally comprisesdeuterium; R¹⁰ and R^(10′) can be independently hydrogen, deuterium,halogen, hydroxy, amino, nitro, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈-cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkykl, aryl, orheteroaryl; n can be an integer from 0-4; and wherein at least one ofR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ or R^(10′) comprises deuterium.In some embodiments, n can be 0 and both R¹⁰ and R^(10′) can behydrogen. In some embodiments, two of R¹, R², R³, R⁴, or R⁵ comprisedeuterium. Also disclosed herein are pharmaceutical compositions thatcomprise an effective amount of the compound, and a pharmaceuticallyacceptable carrier. In some embodiments, the pharmaceutically acceptablecarrier can be dimethyl sulfoxide (DMSO). Also disclosed herein aremethods of treating cancer in a subject in need thereof, that comprisesadministering to the subject the compound the pharmaceuticalcomposition, wherein the method can be effective in treating orameliorating at least one symptom of the cancer in the subject. In someembodiments, the method can further comprise administering to thesubject at least one additional anti-oncologic therapeutic agent. Insome embodiments, the at least one additional anti-oncologic agentcomprises a bRAF inhibitor, an immune checkpoint inhibitor, a caspase-8inhibitor, an ETAR antagonist, niacinamide, a chemotherapeutic agent, orany combination thereof. In some embodiments, the at least oneadditional anti-oncologic agent comprises at least one of the immunecheckpoint inhibitor. In some embodiments, the at least one immunecheckpoint inhibitor comprises at least one anti-PD1 antibody, at leastone anti-PD-L1 antibody, at least one anti-CTLA4 antibody, or anycombination thereof. In some embodiments, the at least one anti-PD1antibody comprises pidilizumab, BMS-936559, nivolumab, pembrolizumab orany combination thereof. In some embodiments, the at least oneanti-PD-L1 antibody compries atezolizumab, avelumab, durvalumab,MDX-1105, or any combination thereof. In some embodiments, the cancercan be a solid tumor cancer, malignant melanoma, metastatic melanoma,malignant squamous cell carcinoma, metastatic squamous cell carcinoma,glioblastoma, brain cancer, pancreatic cancer, colon cancer, breastcancer, ovarian cancer, prostate cancer, or any combination thereof. Insome embodiments, the compound and the at least one additionalanti-oncologic agent can be administered at different times. In someembodiments, the compound can be administered 2, 3, 4, or 5 timesfrequently as the immune checkpoint inhibitor. In some embodiments, thecompound can be administered 3 times frequently as the immune checkpointinhibitor. In some embodiments, the compound can be administered 3 timesevery 2-3 weeks and the immune checkpoint inhibitor can be administered1 time the every 2-3 weeks. In some embodiments, the compound can beadministered 3 times about every 21 days and the immune checkpointinhibitor can be administered 1 time the about every 21 days. In someembodiments, the subject can be a human. In some embodiments, thesubject can be resistant to an immunotherapy before the treatment. Insome embodiments, the administration results in at least one of improvedbiologic activity, increased stability, prolonged serum bioavailability,prolonged ETBR target engagement, or any combination thereof, comparedto a non-deuterated parent compound, as determined by measuring a serumET-1 level. In some embodiments, the administration restores TumorInfiltrating Lymphocytes (TILs), intratumoral tertiary lymphoid organ(TLO) formation, or a combination thereof, in a tumor microenvironment.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate several embodiments of the presentinvention and, together with the description, serve to explain theprinciples of the invention. The drawings are only for the purpose ofillustrating an embodiment of the invention and are not to be construedas limiting the invention. Further objects, features and advantages ofthe invention will become apparent from the following detaileddescription taken in conjunction with the accompanying figures showingillustrative embodiments of the invention, in which:

FIG. 1 shows endothelin B receptor (ETBR) cell signal pathway. ETBR is aseven transmembrane G-protein coupled receptor (GPCR). Endothelin-1(ET-1) is the ligand for the ETBR. Binding of ET-1 to the receptorresults in the activation of a number of downstream kinases, includingPTK, RAF, MEK, MAPK/ERK.

FIG. 2 shows drug resistance to bRAF inhibitors is due to ETBRupregulation. Upregulation of ETBR allows melanoma cells to bypass theblock to MAPK/ERK activation. ETBR antagonists, including specificallydeuterated ETBR antagonists as described herein, block ET-1 binding.

FIG. 3 shows that ET-1 is expressed by advanced melanomas. ET-1 is theligand that activates the ETBR, which causes melanoma cells toproliferate, metastasize, and generate their own blood supply. Thetissue section is from a human invasive melanoma specimen stained withan ET-1 specific label. The photograph indicates that the melanoma ispositive for ET-1. Invasive and metastatic melanomas produce ET-1.

FIGS. 4A and 4B show determination of CXCR4 (h) inhibitory effect for,A) BQ-788 and B) BQ-788-B, a specifically deuterated ETRB antagonist(i.e., “Compound 1”). Cellular agonist effect was calculated as a % ofcontrol response to a known reference agonist for CXCR4 (h), andcellular antagonist effect was calculated as a % inhibition of controlreference agonist response for CXCR4. Results showing ≥50% inhibition ofagonist effect are considered significant while those showing less than25% inhibition are not considered significant. The IC50 for BQ-788 wasgreater than about 1.0E−6 M. The IC50 for BQ-788-B was not calculable.

FIGS. 5A and 5B show determination of ETA (h) inhibitory effect for A)BQ-788 and B) BQ-788-B, a specifically deuterated ETRB antagonist.Cellular agonist effect was calculated as a % of control response to aknown reference agonist for ETA (h), and cellular antagonist effect wascalculated as a % inhibition of control reference agonist response forETA. Results showing ≥50% inhibition of agonist effect are consideredsignificant while those showing less than 25% inhibition are notconsidered significant. The IC50 for BQ-788 and BQ-788-B was notcalculable (i.e., the dose-response curve shows less than 25% effect atthe highest validated testing concentration).

FIG. 6 shows that specifically deuterated ETRB antagonists inhibitmelanoma growth and metastasis and induction of apoptosis in melanomatumor cells. Cellular agonist effect was calculated as a % of controlresponse to a known reference agonist for ETB (h), and cellularantagonist effect was calculated as a % inhibition of control referenceagonist response for ETB. Results showing ≥50% inhibition of agonisteffect are considered significant while those showing less than 25%inhibition are not considered significant. The IC50 for BQ-788 was5.1E−08 M and the Kd was 1.3E−08; while the IC50 for the specificallydeuterated compound is 9.6E−08 M and a Kd of 2.5E−08.

FIG. 7 shows that BQ-788-B, a specifically deuterated ETRB antagonistdemonstrates enhanced biological activity relative to BQ-788. BQ-788-Bdemonstrates a prolonged peak out to about 3 hours as compared toBQ-788, which demonstrates a transient peak at about 30 minutes. TheIC50 for BQ-788-B is 9.6E−08 M (MW=665.37). The IC50 for BQ-788 is5.6E−08 (MW=663.78).

FIG. 8 shows that a dual combination of specifically deuterated ETRBantagonists and an immunotherapeutic results in superior efficacyrelative to current standard drug combinations. The syngeneic melanomamodel V600E+(BRAF mutated) SM1 tumor model was used in C57BL/6 mice toassess efficacy of the specific deuterated ETRB antagonist incombination with the immunotherapeutic (“B+P”) as compared to a standardof treatment, dabrafenib with anti-PD1 (“D+P”).

FIG. 9 shows that a dual combination of the specifically deuterated ETRBantagonist BQ-788-B and immunocheckpoint inhibitors (e.g. anti-PD1)eradicates tumors. Histological examination of V600E+ melanoma tumorcells implanted into C57BL/6 mice 21 days after treatment as indicatedin FIG. 8. BQ-788-B and immunocheckpoint inhibitors in combinationeradicated the tumors in 21 days, promoted robust infiltration by CD8+lymphocytes (TILs), and induced tertiary lymphoid organ (TLO) formation.

FIG. 10 shows intratumoral TLO formation induced by combination therapyincluding the immunocheckpoint inhibitor anti-PD1 and the specificallydeuterated ETRB antagonist BQ-788-B. Histological examination of V600E+melanoma tumor cells implanted into C57BL/6 mice 21 days after treatmentas indicated in FIG. 8 with BQ-788-B and anti-PD1 combination therapy.The staining of CD8+, CD4+ and Treg (FoxP3) lymphocytes indicates thatthe combination therapy promotes strong mobilization of lymphocytes tothe tumor, which is associated with tumor eradication and positivepatient outcomes.

FIG. 11 shows intratumoral (internal) TLO formation associated withtreatment with the specifically deuterated compound BQ-788-B. The tablessummarize results obtained with combination therapies (two- andthree-part), TLO formation and efficacy for tumor eradication. The dataindicate that (i) internal TLO formation is associated with tumorreduction; and (ii) the combination immunocheckpoint inhibitors andBQ-788-B was most frequently associated with intratumoral TLO formationand tumor reduction.

FIG. 12 shows that the inclusion of the specifically deuterated ETRBantaonist BQ-788-B with the immunocheckpoint inhibitor anti-PD1 restoressensitivity to anti-PD1. The addition of dabrafenib to anti-PD1/BQ-788-Bcombination impairs efficacy, possibly due to dabrafenib's ability toincrease Tregs and tumor-associated macrophages (TAMs).

FIG. 13 shows that specifically deuterated compound BQ-788-B at 0.6 μgin combination with immunocheckpoint inhibitor (e.g. anti-CTLA,anti-PD-L1, or anti-PD1) and dabrafenib promotes diffuse CD8+ TILstaining. Histological examination of V600E+ melanoma tumor cellsimplanted into C57BL/6 mice 21 days after treatment as indicated in FIG.8 with the respective combination therapy. The diffuse distribution ofCD8+ TIL staining (dark punctate staining in “D+P+B (0.6 μg)”) appearsto be associated with higher efficacy as compared to those withperipheral distribution of TILs (see “D+P+B (4.0 μg)” and “D+P+B (100μg)”).

FIG. 14 depicts an exemplary synthetic scheme for preparation ofspecifically deuterated ETRB antagonists.

FIG. 15 depicts an exemplary synthetic scheme for preparation ofintermediates for synthesis of specifically deuterated ETRB antagonists.

FIG. 16 depicts an exemplary synthetic scheme for preparation ofintermediates for synthesis of the specifically deuterated ETRBantagonists BQ-788-A and BQ-788-C.

FIG. 17 depicts an exemplary synthetic scheme for preparation of thespecifically deuterated ETRB antagonist BQ-788-A.

FIG. 18 depicts an exemplary synthetic scheme for preparation of thespecifically deuterated ETRB antagonist BQ-788-C.

DETAILED DESCRIPTION

Disclosed herein are specifically deuterated ETBR antagonist compounds,compositions, and methods useful for the treatment of cancer for examplean ETBR-related cancer, e.g., malignant melanoma, metastatic melanoma,squamous cell carcinoma, glioblastoma, ovarian cancer, pancreaticcancer, or any combination thereof. As described herein, specificallydeuterated ETBR antagonists as formulated herein are surprisinglyadvantageous for treating ETBR-related cancers. The use of aspecifically deuterated ETBR antagonist significantly improves biologicactivity relative to the non-deuterated parent compound, as determinedby measuring serum ET-1 levels, and results in at least one of increasedstability, prolonged serum bioavailability, prolonged ETBR targetengagement, or any combination thereof. In some embodiments, the subjecttreated is resistant to an immunotherapy. In some embodiments, thecomposition and method disclosed herein restores Tumor InfiltratingLymphocytes (TILs) and/or intratumoral tertiary lymphoid organ (TLO)formation in a tumor microenvironment.

Also disclosed herein is a combination that comprises at least onespecifically deuterated ETBR antagonist as disclosed herein, and atleast one additional anti-oncologic therapeutic agent, administeredeither at the same time or at different times. In some embodiments, theat least one anti-oncologic agent comprises a bRAF inhibitor, an immunecheckpoint inhibitor, a caspase-8 inhibitor, an ETAR antagonist,niacinamide, a chemotherapeutic agent such as, e.g., a taxane, a kinaseinhibitor, or other receptor antagonist or combination thereof. In someembodiments, the at least one anti-oncologic agent is an immunecheckpoint inhibitor. In some embodiments, the immune checkpointinhibitor is an anti-PD1 antibody or an anti-PD-L1 antibody. In someembodiments, the anti-PD1 antibody is nivolumab, pembrolizumab,pidilizumab, cemiplimab, or any combination thereof. In someembodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105,avelumab, durvalumab, or any combination thereof. In some embodiments,specifically deuterated ETRB antagonists as described herein andanti-oncologic agents (i.e. immunocheckpoint inhibitors such asanti-anti-CTLA, anti-PDL1, and anti-PD1 antibodies) can be administeredat the same time (e.g. simultaneously. In some embodiments, specificallydeuterated ETRB antagonists as described herein and anti-oncologicagents (i.e. immunocheckpoint inhibitors such as anti-CTLA, anti-PDL1,and anti-PD1 antibodies) can be administered at the different times(e.g. simultaneously. In some embodiments, the specifically deuteratedETBR antagonist can be administered once weekly, biweekly, monthly, orbimonthly. In some embodiments, the anti-oncologic agent (i.e.immunocheckpoint inhibitors such as anti-CTLA, anti-PDL1, and anti-PD1antibodies) can be administered once weekly, biweekly, monthly, orbimonthly. In some embodiments, the specifically deuterated ETBRantagonist is administered 2, 3, 4, or 5 times frequently as theadditional anti-oncologic agent, for example that the deuterated ETBRantagonist is administered 3 times during 2-3 weeks (e.g., 21 days)while the additional anti-oncologic agent is administered 1 time duringthe 2-3 weeks (e.g., the 21 days). In some embodiments, the combinationcomprises an effective amount of the at least one deuterated ETBRantagonist and an effective amount of the at least one anti-oncologicagent. In some embodiments, the combination includes a pharmaceuticallyacceptable carrier for example DMSO. In some embodiments, thecombination is in separate unit dosage forms, for example, a firstcontainer that comprises the at least one specifically deuterated ETBRantagonist, and a second container that comprises the at least oneanti-oncologic agent. In some embodiments, the active agents disclosedherein are in a controlled-release delivery system comprises at leastone of: (1) a biocompatible polymer, (2) a liposome preparation; (3) aDMSO solution, or a combination thereof.

Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The terminology used in thedescription is for describing particular embodiments only and is notintended to be limiting of the invention.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the invention. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the present disclosure.

The articles “a” and “an” as used herein and in the appended claims areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e., “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.”

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from anyone or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anonlimiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, in certain methods described hereinthat include more than one step or act, the order of the steps or actsof the method is not necessarily limited to the order in which the stepsor acts of the method are recited unless the context indicatesotherwise.

The term “combination therapy” refers to both concurrent administration(administration of two or more therapeutic agents at the same time) andtime varied administration (administration of one or more therapeuticagents at a time different from that of the administration of anadditional therapeutic agent or agents). In some embodiments, thetherapeutic agents are present in the patient to some extent, forexample at effective amounts, at the same time. In some embodiments, oneor more of the compounds described herein, are administered incombination with at least one additional bioactive agent, especiallyincluding an anticancer agent. In some embodiments, the combinationtherapy of compounds results in synergistic activity, includinganticancer activity.

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,stereoisomers, including optical isomers (enantiomers) and othersteroisomers (diastereomers) thereof, as well as pharmaceuticallyacceptable salts and derivatives (including prodrug forms) thereof whereapplicable, in context. Within its use in context, the term compoundgenerally refers to a single compound, but also may include othercompounds such as stereoisomers, regioisomers and/or optical isomers(including racemic mixtures) as well as specific enantiomers orenantiomerically enriched mixtures of disclosed compounds. The term alsorefers, in context to prodrug forms of compounds which have beenmodified to facilitate the administration and delivery of compounds to asite of activity. It is noted that in describing the present compounds,numerous substituents and variables associated with same, among others,are described. It is understood by those of ordinary skill thatmolecules which are described herein are stable compounds as generallydescribed hereunder. When the bond is shown, both a double bond andsingle bond are represented within the context of the compound shown.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment of anydisease state or condition which is modulated through the protein towhich the present compounds bind. Disease states or conditions,including cancer, which may be treated using compounds according to thepresent disclosure, are set forth hereinabove.

The term “anti-oncologic agent” is used to describe an anti-canceragent, which may be combined with compounds according to the presentdisclosure to treat cancer. These agents include, for example,everolimus, niacinamide, trabectedin, abraxane, TLK 286, AV-299, DN-101,pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886),AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197,MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFRinhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, aPARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TKinhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKTinhibitor, an mTORC 1/2 inhibitor, a JAK/STAT inhibitor, a checkpoint-1or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase(mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib,nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu,nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin,tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab,ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490,cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402,lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel,atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil,vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethyl stilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib, AG-013736,AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate,medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrolacetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrolacetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib,ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib,BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analidehydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds described herein which are presented to increase thesolubility of the compound in the gastric juices of the patient'sgastrointestinal tract in order to promote dissolution and thebioavailability of the compounds. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids, where applicable. Suitable salts include thosederived from alkali metals such as potassium and sodium, alkaline earthmetals such as calcium, magnesium and ammonium salts. In someembodiments, sodium and potassium salts are suitable neutralizationsalts of the phosphates.

The term “pharmaceutically acceptable derivative” is used throughout thespecification to describe any pharmaceutically acceptable prodrug form(such as an ester, amide other prodrug group), which, uponadministration to a patient, provides directly or indirectly the presentcompound or an active metabolite of the present compound.

The term “effective” is used to describe an amount of a compound,composition or component which, when used within the context of itsintended use, effects an intended result. The term “effective” subsumesall other effective amount or effective concentration terms, which areotherwise described or used in the present application.

The term “therapeutically effective amount” refers to that amount whichis sufficient to effect treatment, as defined herein, when administeredto a mammal in need of such treatment.

The term “patient” or “subject” is used throughout the specification todescribe an animal, for example a human, or a domesticated animal, towhom treatment, including prophylactic treatment, with the compositionsaccording to the present disclosure is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient, the term patient refers to thatspecific animal, including a domesticated animal such as a dog or cat ora farm animal such as a horse, cow, sheep, etc. In general, in thepresent disclosure, the term patient refers to a human patient unlessotherwise stated or implied from the context of the use of the term.Activation of the ETBR by endothelins such as ET-1 and ET-3, results ina variety of molecular events that promote melanoma invasion andmetastasis. Without being bound by any particular theory, it ishypothesized that while the majority of melanomas express ETBR, a subsetof these also expresses the ETBR activator ET-1 and/or ET-3. It is thissubset that is therefore most likely dependent upon ETBR activation forviability, invasive potential and metastatic potential. Thus, thissubset of patients is most likely to respond to ETBR blockade.Furthermore, this subset of patients is least likely to response toimmune based therapy.

The Endothelin B receptor (ETBR) pathway (FIG. 1) plays a significantrole in the metastatic spread of melanoma, and therefore, is a targetfor therapeutic intervention. The Endothelin B receptor is a 7transmembrane G-protein coupled receptor (GPCR). It is expressed at verylow levels in normal melanocytes, but is upregulated during melanomadevelopment and progression. RAF and MEK kinases, current melanoma drugtargets, are activated by the deuterated ETBR. The specific deuteratedare beneficial because, as compared to nondeuterated, there is animprovement in one or more pharmaceutical properties (e.g. efficacy,solubility)

Endothelin-1 (ET-1) (and Endothelin-3, not shown) is a ligand thatactivates the ETBR (FIG. 2). ET-1 activation of ETBR causes melanomacells to proliferate, metastasize and generate their own blood supply.Our studies show that the majority of pigmented invasive melanomas andmetastatic melanomas produce ET-1 (FIG. 3).

Deuterated Compounds (Specific)

Disclosed herein is a specifically deuterated ETBR antagonist, e.g., adeuterated form of BQ-788 as described herein. In some embodiments, thedescription provides a composition comprising at least one specificallydeuterated ETBR antagonist, e.g., a deuterated form of BQ-788 asdescribed herein, and a pharmaceutically acceptable carrier. In someembodiments, the description provides a composition, e.g., apharmaceutical composition, comprising an effective amount of at leastone specifically deuterated ETBR antagonist, e.g., a deuterated form ofBQ-788 as described herein, and a pharmaceutically acceptable carrier.In some embodiments, the pharmaceutical composition as described hereincan be in unit dosage form configured for administration one or moretimes, for example, one or more times per day, per week, or per month.

In some embodiments, the specifically deuterated ETBR antagonist is acompound of the Formula (1) below:

whereinn is an integer from 0-5;m is an integer from 0-3;X is a positively charged counterion;R₁ and R₃ are independently —H, -D, —CH₃, —CH₂D, —CHD₂, or —CD₃;R_(2a), R_(2b), R₄, R₅, and R₆ are independently —CH₃, —CH₂D, —CHD₂, or—CD₃; andat least one of R₁, R₂, or R₃ comprises deuterium.

In some embodiments, the specifically deuterated ETBR antagonist offormula (1) comprises 1-8 deuterium atoms. In specific embodiments, thespecifically deuterated ETBR antagonist of formula (1) comprises 1, 2,or 3 deuterium atoms.

In some embodiments, the specifically deuterated ETBR antagonist is acompound of the Formula (2) below:

In some embodiments, the specifically deuterated ETBR antagonist is acompound of the Formula (3) below:

In some embodiments, the specifically deuterated ETBR antagonist is acompound of the Formula (4) below:

In some embodiments, the specifically deuterated ETBR antagonist is acompound of the Formula (5) below:

In some embodiments, the specifically deuterated ETBR antagonist is acompound of the formula (6) below:

In some embodiments, the specifically deuterated ETBR antagonist offormula (6), n is 0 or 1.

In some embodiments of the specifically deuterated ETBR antagonist offormula (6), n is 1 and R1 is -D.

In some embodiments of the specifically deuterated ETBR antagonist offormula (6), n is 1, R₁ is -D; and R_(2a) and R_(2b) are —CH₃.

In some embodiments of the specifically deuterated ETBR antagonist offormula (6), n is 0, R₁ is —H; R_(2a) is —CH₃ and R_(2b) is —CH₂D.

In some embodiments of the specifically deuterated ETBR antagonist offormula (6), n is 0, R₁ is —H; R_(2a) is —CH₂D and R_(2b) is —CH₃.

In some embodiments of the specifically deuterated ETBR antagonist offormula (6), n is 0, R₁ is —H; and R_(2a) and R_(2b) are —CH₂D.

In some embodiments of the specifically deuterated ETBR antagonist offormula (6), n is 1, R₁ is -D; and R_(2a) and R_(2b) are —CH₂D.

In some embodiments, the specifically deuterated ETBR antagonist is atleast one of BQ-788-A, BQ-788-B, BQ-788-C, or a combination thereof,including analogs, derivatives, polymorphs, prodrugs, and salts thereof,including fluorinated analogues. For example, the specificallydeuterated ETBR antagonist can be a fluorinated analog of BQ-788-A,BQ-788-B, or BQ-788-C.

In some embodiments, BQ-788-A is a specifically deuterated ETBRantagonist depicted below:

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, BQ-788-B is a specifically deuterated ETBRantagonist depicted below:

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, BQ-788-C is a specifically deuterated ETBRantagonist depicted below:

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound disclosed here is of Formula (7):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

-   -   wherein:        -   each of R¹, R², R³, R⁴, or R⁵ is independently hydrogen,            halogen, hydroxyl, deuterium, halogen, hydroxy, amino,            nitro, optionally substituted C₁-C₈ alkyl, optionally            substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈            alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally            substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈            haloalkykl, optionally substituted aryl, or optionally            substituted heteroaryl, optionally wherein one or more of            the carbons in the piperidinyl ring can be a heteroatom            selected from O, N, or S, or wherein the piperidinyl ring            may contain one or more double bonds;        -   R⁶ is optionally substituted C₁-C₈ alkyl, optionally            substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈            alkynyl, optionally substituted C₃-C₈-cycloalkyl, optionally            substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈            haloalkykl, optionally substituted aryl, or optionally            substituted heteroaryl, wherein R⁶ optionally comprises            deuterium;        -   R⁷ is optionally substituted cycloalkyl, optionally            substituted heterocycloalkyl, optionally substituted aryl,            optionally substituted heteroaryl, optionally substituted            polycyclic ring system, optionally substituted bicyclic,            optionally substituted heterobicyclic, wherein R⁷ optionally            comprises deuterium;        -   R⁸ and R⁹ are independently optionally substituted C₁-C₈            alkyl, optionally substituted C₂-C₈ alkenyl, optionally            substituted C₂-C₈ alkynyl, optionally substituted C₃-C₈            cycloalkyl, optionally substituted C₁-C₈ alkoxy, optionally            substituted C₁-C₈ haloalkyl, optionally substituted aryl,            optionally substituted heteroaryl, or —COOR′, or R⁸ and R⁹            may be taken together to form a optionally substituted            cycloalkyl, optionally substituted cycloalkyl            heterocycloalkyl, optionally substituted aryl, optionally            substituted heteroaryl, or optionally substituted polycyclic            ring system, wherein R⁸ or R⁹ each optionally comprises            deuterium;        -   R′ is hydrogen, hydroxy, or C₁-C₈ alkyl; and        -   wherein at least one of R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, or R⁹ is            deuterium.

In some embodiments, a compound disclosed here is of Formula (8):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

-   -   wherein:        -   each of R², R³, or R⁴ is independently hydrogen, deuterium,            halogen, hydroxy, amino, nitro, C₁-C₈ alkyl, C₂-C₈ alkenyl,            C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₁-C₈ alkoxy, C₁-C₈            haloalkykl, aryl, or heteroaryl;        -   R⁶ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈            cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkykl, aryl, or            heteroaryl, wherein R⁶ optionally comprises deuterium;        -   R⁷ is substituted or unsubstituted cycloalkyl, substituted            or unsubstituted heterocycloalkyl, substituted or            unsubstituted aryl, substituted or unsubstituted heteroaryl,            or a substituted or unsubstituted polycyclic ring system,            wherein R⁷ optionally comprises deuterium;        -   R⁸ and R⁹ are independently C₁-C₈ alkyl, C₂-C₈ alkenyl,            C₂-C₈ alkynyl, C₃-C₈-cycloalkyl, C₁-C₈ alkoxy, C₁-C₈            haloalkykl, aryl, heteroaryl, or —COOR′, or R⁸ and R⁹ may be            taken together to form a substituted or unsubstituted            cycloalkyl, substituted or unsubstituted cycloalkyl            heterocycloalkyl, substituted or unsubstituted aryl,            substituted or unsubstituted heteroaryl, or substituted or            unsubstituted polycyclic ring system, wherein R⁸ or R⁹ each            optionally comprises deuterium;        -   R′ is hydrogen, hydroxy, or C₁-C₈ alkyl; and        -   wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, or            R⁹ is deuterium.

In some embodiments, a compound disclosed here is Formula (9):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

-   -   wherein:        -   each of R¹ R², R³, R⁴, or R⁵ is independently hydrogen,            deuterium, halogen, hydroxy, amino, nitro, C₁-C₈ alkyl,            C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₁-C₈            alkoxy, C₁-C₈ haloalkyl, aryl, or heteroaryl;        -   R⁶ is C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,            C₃-C₈-cycloalkyl, C₁-C₈ alkoxy, C₁-C₈ haloalkykl, aryl, or            heteroaryl, wherein R⁶ optionally comprises deuterium;        -   R⁸ and R⁹ are independently C₁-C₈ alkyl, C₂-C₈ alkenyl,            C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, R⁸ and R⁹ are independently            C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈-cycloalkyl,            C₁-C₈ alkoxy, C₁-C₈ haloalkykl, aryl, heteroaryl, or —COOR′,            or R⁸ and R⁹ may be taken together to form a substituted or            unsubstituted cycloalkyl, substituted or unsubstituted            cycloalkyl heterocycloalkyl, substituted or unsubstituted            aryl, substituted or unsubstituted heteroaryl, or            substituted or unsubstituted polycyclic ring system, wherein            R⁸ or R⁹ each optionally comprises deuterium;        -   R¹⁰ and R^(10′) are independently hydrogen, deuterium,            halogen, hydroxy, amino, nitro, C₁-C₈ alkyl, C₂-C₈ alkenyl,            C₂-C₈ alkynyl, C₃-C₈-cycloalkyl, C₁-C₈ alkoxy, C₁-C₈            haloalkykl, aryl, or heteroaryl;        -   n is an integer from 0-4; and        -   wherein at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,            R¹⁰ or R^(10′) is deuterium.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising at least onespecifically deuterated ETBR antagonist, e.g., a deuterated form ofBQ-788 as described herein, and a pharmaceutically acceptable carrier.

In some embodiments, the compositions herein are formulated in a unitdosage form, including any desired carrier or excipient, and configuredfor administration via any desired route, e.g., oral, intravenous,subcutaneous, intramuscular, intraperitoneal, parenteral, intranasal,intracranial.

In some embodiments, the compositions as described herein are useful forthe treatment of ETBR-related cancer in a patient. In some embodiments,the cancer is a solid tumor. In some embodiments, the cancer is at leastone of breast cancer, melanoma, SCC, glioblastoma, ovarian cancer,pancreatic cancer, or a combination thereof.

In some embodiments, the compositions comprise a dosage of thespecifically deuterated ETBR antagonist of about 0.1 mg to about 500 mg(e.g., about 10 mg to about 100 mg), and/or a concentration of thespecifically deuterated ETBR antagonist of about 0.01 g/mL to about 1000mg/mL (e.g., about 0.1 mg/mL to about 5 mg/mL).

In some embodiments, the compositions as described herein are formulatedin a conventional manner using one or more pharmaceutically acceptablecarriers and may also be administered in controlled-releaseformulations. Pharmaceutically acceptable carriers that may be used inthese pharmaceutical compositions include, but are not limited to,dimethyl sulfoxide (DMSO), soybean oil as a carrier, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

In some embodiments, the compositions include at least one of soybeanoil, dimethyl sulfoxide (DMSO), hydrogel, or a combination thereof. Anyof the embodiments described herein can be a single-component oil phaseformulation, as described above, wherein each active ingredient can beat any of the dosages or concentrations described herein. Thesingle-component oil phase can be a fixed oil, such as soybean oil. Forexample, the formulation comprises about 0.1 mg to about 5.0 mg of eachactive ingredient in 1 mL of the single-component oil (i.e., about 0.5mg/mL, about 1 mg/mL, or about 1.5 mg/mL of each active ingredient inthe single-component oil). The single-component oil phase formulationcan be prepared by adding each active ingredient (e.g., about 1 mg toabout 50 mg of each of the active ingredient(s)) to about 10 mL of thesingle-component oil solution.

In some embodiments, pharmaceutical compositions herein comprise a DMSO,e.g., in a DMSO solution that is about 5% to about 100% DMSO (e.g.,about 10% to about 100%, about 20% to about 100%, about 30% to about100%, about 40% to about 100%, about 50% to about 100%, about 60% toabout 100%, about 70% to about 100%, about 80% to about 100%, about 90%to about 100%, about 30% to about 95%, about 45% to about 95%, about 75%to about 95%, about 30% to about 90%, about 45% to about 90%, about 75%to about 90%, about 30% to about 85%, about 45% to about 85%, or about75% to about 85%). For example, the pharmaceutical compositionscomprises about 0.1 mg to about 5.0 mg of each active ingredient in 1 mLof DMSO (i.e., about 0.5 mg/mL, about 1 mg/mL, or about 1.5 mg/mL ofeach active ingredient in DMSO). The DMSO pharmaceutical compositionscan be prepared by adding each active ingredient (e.g., about 1 mg toabout 50 mg of each of the active ingredient(s)) to about 10 mL of theDMSO solution. For example, the DMSO is a DMSO solution comprising about5% to about 100% DMSO, about 25% to about 100% DMSO, about 50% to about100% DMSO, about 75% to about 100% DMSO, about 5% to about 75% DMSO,about 25% to about 75% DMSO, about 50% to about 75% DMSO, about 5% toabout 50% DMSO, about 25% to about 50% DMSO, or about 5% to about 25%DMSO.

In some embodiments, the description provides a controlled releasesubcutaneous or intramuscular dosage formulation comprising a uniformdispersion of a specifically deuterated ETBR antagonist (e.g., BQ-788,BQ-017, A192621, a deuterated or fluorinated analog thereof, orcombinations thereof) and an ETAR antagonist (e.g., BQ123) in abiocompatible delivery system whereby following administration thedeuterated ETBR and ETAR antagonists are released slowly andsimultaneously from the formulation into the systemic circulation.

In some embodiments, the pharmaceutical composition as described hereinis formulated into a controlled release delivery system comprising atleast one biocompatible polymer. In some embodiments, the activecompounds are prepared with carriers that will protect the compoundagainst rapid elimination from the body, such as a controlled releaseformulation, including implants, hydrogels, thermo-sensitive hydrogels,and microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, acrylates,polycarboxylic acids, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. In some embodiments, thebiocompatible polymer is at least one of a poly(lactide),poly(glycolide), poly(lactide-co-glycolide), poly(lactic acid),poly(glycolic acid), poly(lactic acid-co-glycolic acid),polycaprolactone, polycarbonate, polyesteramide, polyanhydride,poly(amino acid), polyorthoester, polycyanoacrylate, poly(p-dioxanone),poly(alkylene oxalate), biodegradable polyurethane, blend, or acopolymer thereof.

In some embodiments, the pharmaceutically acceptable carrier comprisesor is a liposome. For example, the pharmaceutical composition orformulation may comprise a liposome having an interior volume comprisinga specifically deuterated ETBR antagonist. In some embodiments, theliposome is configured to effectuate the controlled release of thespecifically deuterated ETBR antagonist, e.g., rapid release, extendedrelease, or a combination thereof.

In some embodiments, the liposome is configured to effectuate thecontrolled release of the pharmaceutical compositions. In someembodiments, the liposome is configured to effectuate rapid release ofthe pharmaceutical compositions. In other embodiments, the liposome isconfigured or formulated to effectuate extended release thepharmaceutical compositions. In some embodiments, the liposome isconfigured to result in both the rapid and extended release ofpharmaceutical compositions.

In some embodiments, the liposome is configured to effectuate thecontrolled release of the specifically deuterated ETBR antagonist or thecaspase-8 inhibitor or a combination thereof. In some embodiments, theliposome is configured to effectuate rapid release of the specificallydeuterated ETBR antagonist or the caspase-8 inhibitor or a combinationthereof. In other embodiments, the liposome is configured or formulatedto effectuate extended release the specifically deuterated ETBRantagonist or the caspase-8 inhibitor or a combination thereof. In someembodiments, the liposome is configured to result in both the rapid andextended release of the specifically deuterated ETBR antagonist or thecaspase-8 inhibitor or a combination thereof.

In some embodiments, liposomal suspensions are pharmaceuticallyacceptable carriers. For example, liposome formulations may be preparedby dissolving appropriate lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent that is thenevaporated, leaving behind a thin film of dried lipid on the surface ofthe container. An aqueous solution of the active compound is thenintroduced into the container. The container is then swirled by hand tofree lipid material from the sides of the container and to disperselipid aggregates, thereby forming the liposomal suspension.

In some embodiments, the pharmaceutical compositions comprise a liposomehaving an interior volume comprising a specifically deuterated ETBRantagonist or a caspase-8 inhibitor or a combination thereof, and aneffective amount of at least one of an ETAR antagonist, an anti-PD1antibody, a bRAF inhibitor, niacinamide or a combination thereof. Insome embodiments, the liposome comprises at least one of a neutrallipid, a basic (having a net positive charge) lipid, an acidic (having anet negative charge) lipid, cholesterol, or a combination thereof. Insome embodiments, the liposome further comprises a polymeric component.In some embodiments, the interior volume of the liposome is at leastpartially aqueous, and comprises a specifically deuterated ETBRantagonist.

In some embodiments, the description provides the pharmaceuticalcomposition as described herein in a liposomal delivery system, e.g., atleast one of a phosphatidylethanol amine (PE) such as dipalmitoyl PE(DPPE), and partially unsaturated phosphatidylcholine (PC), such as eggPC (EPC) or SPC, fully unsaturated PC such as HSPC, PG,phosphatidylserine (PS), phosphatidylinositol (PI) or a combinationthereof. In some embodiments, the phospholipid is at least one of apartially unsaturated PG, dipalmitoylphosphatidylglycerol (DPPG),cholesterol, DSPE-PEG2000, polysorbate-80 or combination thereof. Insome embodiments, the liposomal delivery system is a controlled releasesystem, e.g., at least one of rapid release, extended release, rapid andextended release, delayed release, sustained release, slow release, andcombinations thereof.

In some embodiments, the pharmaceutical compositions herein comprisepharmaceutically acceptable salts, in particular, acid or base additionsalts of compounds as described herein. The acids which are used toprepare the pharmaceutically acceptable acid addition salts of theaforementioned base compounds useful according to this aspect are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bitartrate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3 naphthoate)]salts, among numerousothers. Pharmaceutically acceptable base addition salts may also be usedto produce pharmaceutically acceptable salt forms of the compounds orderivatives according to the present disclosure. The chemical bases thatmay be used as reagents to prepare pharmaceutically acceptable basesalts of the present compounds that are acidic in nature are those thatform nontoxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (eg.,potassium and sodium) and alkaline earth metal cations (e.g., calcium,zinc and magnesium), ammonium or water-soluble amine addition salts suchas N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines, amongothers.

In some embodiments, oral compositions include an inert diluent or anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theactive compound or its prodrug derivative can be incorporated withexcipients and used in the form of tablets, troches, or capsules.Pharmaceutically compatible binding agents, and/or adjuvant materialscan be included as part of the composition. The tablets, pills,capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a dispersing agent such as alginic acid, Primogel,or corn starch; a lubricant such as magnesium stearate or Sterotes; aglidant such as colloidal silicon dioxide; a sweetening agent such assucrose or saccharin; or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it can contain, in addition to material of the above type, a liquidcarrier such as a fatty oil. In addition, dosage unit forms can containvarious other materials which modify the physical form of the dosageunit, for example, coatings of sugar, shellac, or enteric agents.

In some embodiments, the active compound or pharmaceutically acceptablesalt thereof is administered as a component of an elixir, suspension,syrup, wafer, chewing gum or the like. A syrup may contain, in additionto the active compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

In some embodiments, solutions or suspensions used for parenteral,intradermal, subcutaneous, intravenous, intramuscular, or topicalapplication include the following components: a sterile diluent such aswater for injection, saline solution, fixed oils (e.g., soybean oil),polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic. In some embodiments, carriers for intravenousadministration are physiological saline or phosphate buffered saline(PBS).

Combination Therapy

Disclosed herein are pharmaceutical compositions for therapeuticcombinations, in a single dosage form or separate dosage formsadministered concurrently or separately, comprising at least one ofspecifically deuterated ETBR antagonist as described herein, and atleast one additional anti-oncologic agent. In some embodiments, the atleast one additional anti-oncologic agent is an immune checkpointinhibitor, e.g., an anti-PD1 antibody or anti-PD-L1 antibody. In someembodiments, the specifically deuterated ETBR antagonist is administered2, 3, 4, or 5 times frequently as the additional anti-oncologic agent,for example that the specifically deuterated ETBR antagonist isadministered 3 times during 1-3 weeks (e.g, about 2-3 weeks or about 21days) while the additional anti-oncologic agent is administered 1 timeduring the 1-3 weeks (e.g., about 2-3 weeks or about 21 days).

In some embodiments, the pharmaceutical compositions as described hereindemonstrate a synergistic effect in that the pharmaceutical compositionsachieve at least one of: a greater therapeutic effect (i.e., moreefficacious) than the additive therapeutic effect obtained byadministration of the constituent ingredients alone, a greatertherapeutic effect than achieved by administration of a higher dose ofthe constituent ingredients alone, a similar or greater therapeuticeffect but with a decrease in adverse events or side effects relative tothat observed by administration of the constituent ingredients alone(i.e., improved therapeutic window), or increased duration of effects,or a similar or greater therapeutic effect at a smaller dose of one orboth of the constituent ingredients or a combination thereof.

In some embodiments, the description provides pharmaceuticalcompositions comprising a first composition comprising a specificallydeuterated ETBR antagonist as described herein in an amount effectivewhen administered with at least one additional anticancer oranti-oncologic agent; and a second composition comprising an effectiveamount of the at least one additional anticancer or anti-oncologic agentas described herein.

In some embodiments, the description provides a combination comprisingat least one ETBR antagonist, e.g., a specifically deuterated ETBRantagonist, and at least one additional anti-oncologic therapeuticagent. In some embodiments, the at least one anti-oncologic agent is abRaf inhibitor, an immune checkpoint inhibitor, a caspase-8 inhibitor,an ETAR antagonist, niacinamide, a chemotherapeutic agent such as, e.g.,a taxane, a kinase inhibitor, or other receptor antagonist orcombination thereof. In some embodiments, the pharmaceuticalcompositions comprise an effective amount (e.g., a synergisticallyeffective amount) of at least two of specifically deuterated ETBRantagonist, bRaf inhibitor, an immune checkpoint inhibitor, a caspase-8inhibitor, an ETAR antagonist, niacinamide, a chemotherapeutic agentsuch as, e.g., a taxane, a kinase inhibitor, or other receptorantagonist or combination thereof.

In some embodiments, the specifically deuterated ETBR antagonist and theat least one additional anti-oncologic therapeutic agent are comprisedin separate pharmaceutical compositions. In some embodiments, thespecifically deuterated ETBR antagonist and the at least one additionalanti-oncologic therapeutic agent are comprised in the samepharmaceutical composition.

In some embodiments, the description provides methods comprisingadministering a specifically deuterated ETBR antagonist as describedherein in an amount effective for treating cancer and an anti-oncologicagent, and a pharmaceutically acceptable excipient or carrier. In someembodiments, the specifically deuterated ETBR antagonist is at least oneof a deuterated BQ-788, BQ-017, A192621, BQ-788-A, BQ-788-B, or BQ-788-Cor a combination thereof.

In some embodiments, the description provides a pharmaceuticalcomposition comprising a specifically deuterated ETBR antagonist asdescribed herein in an amount effective for treating cancer, and apharmaceutically acceptable carrier. In some embodiments, the amount iseffective to treat cancer when also administered with at least oneadditional anti-oncologic agent, and a pharmaceutically acceptableexcipient or carrier. In some embodiments, the specifically deuteratedETBR antagonist is at least one of a deuterated BQ-788, BQ-017, A192621,BQ-788-A, BQ-788-B, or BQ-788-C or a combination thereof.

In some embodiments, the description provides a therapeutic combinationcomprising, in the same or separate dosage forms, an effective amount ofthe at least one ETBR antagonist and an effective amount of at least oneanti-oncologic agent. In some embodiments, the combination comprises asynergistically effective amount of the at least one ETBR antagonist. Insome embodiments, the combination comprises a synergistically effectiveamount of the at least one anti-oncologic agent. In some embodiments,the combination includes a pharmaceutical acceptable carrier. In someembodiments, the combination or formulation is comprised in one or moreunit dosage forms. In further embodiments, the combination is comprisedin separate unit dosage forms, for example, a first container comprisingthe at least one ETBR antagonist, and a second container comprising theat least one anti-oncologic agent. In some embodiments, the ETBRantagonist is a specifically deuterated ETBR antagonist as describedherein.

In some embodiments, the description provides a combination therapycomprising administering: (a) a first composition comprising aneffective amount of a specifically deuterated ETBR antagonist and apharmaceutically acceptable carrier or excipient; and (b) a secondcomposition comprising an effective amount of at least one additionalanti-oncologic agent, and a pharmaceutically acceptable carrier orexcipient, wherein the administering demonstrates synergisticanti-cancer activity. In some embodiments, the specifically deuteratedETBR antagonist is a deuterated BQ-788 as described herein.

In some embodiments, the at least one anti-oncologic agent is an immunecheckpoint inhibitor. In some embodiments, the immune checkpointinhibitor is an anti-PD1 antibody or an anti-PD-L1 antibody. In someembodiments, the anti-PD1 antibody is at least one of nivolumab,pembrolizumab, pidilizumab, or any combination thereof. In someembodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105,avelumab, durvalumab, or any combination thereof.

In some embodiments, the bRAF inhibitor is at least one of dabrafenib,sorafenib, vemurafenib, or any other bRAF inhibitor known or thatbecomes known to one skilled in the art.

In some embodiments, caspase-8 is a downstream effector of the ETBR, andcaspase-8 inhibitors block molecular events that promote invasion andmetastasis that are triggered as a result of ETBR activation. As such,caspase-8 inhibitors can be classified as a caspase-8 antagonist or anantagonist/inhibitor of ETBR signaling. In some embodiments, thecaspase-8 inhibitor peptide has a sequence ofAc-AAVALLPAVLLAALAPIETD-CHO (SEQ ID NO: 1), which is commerciallyavailable from EMD Millipore (Billerica, Mass. 01821, USA).

In some embodiments, the physiologic role of the ETBR is to clear excesslevels of endothelin-1 (ET-1), from the circulation. Without being boundby any particular theory, it is hypothesized that administering aspecifically deuterated ETBR antagonist prevents ET-1 clearance andelevates serum ET-1 levels. Elevated serum levels of ET-1 are associatedwith a variety of adverse effects due to its activation of theEndothelin A receptor (ETAR) including, hypertension, pulmonaryhypertension and renal vasoconstriction. In some embodiments, in orderto minimize the unwanted effect of ETAR activation, the descriptionprovides pharmaceutical compositions and methods for combination therapy(in a single dosage form or separate dosage forms administeredapproximately contemporaneously) of a specifically deuterated ETBRantagonist with an ETAR antagonist. The ETAR antagonist actssynergistically to enhance the beneficial effects of a specificallydeuterated ETBR antagonist while minimizing adverse events or sideeffects. It was also surprising that an effective amount (e.g., asynergistically effective amount) of niacinamide was effective atsynergistically minimizing adverse events or side effects, such asweight loss, from the specifically deuterated ETBR antagonist. Theformulations as described herein are useful for the treatment of cancerin a patient, for example, breast cancer, melanoma, SCC, glioblastoma;solid tumors or a combination thereof.

In some embodiments, the ETAR antagonist is BQ123. BQ123(2-[(3R,6R,9S,12R,15S)-6-(1H-indol-3-ylmethyl)-9-(2-methylpropyl)-2,5,8,11,14-pentaoxo-12-propan-2-yl-1,4,7,10,13-pentazabicyclo[13.3.0]octadecan-3-yl]aceticacid or cyclo(D-Trp-D-Asp-Pro-D-Val-Leu)) is a selective ETARantagonist. (Ishikawa et al., (1992). “Cyclic pentapeptide endothelinantagonists with high ETA selectivity. Potency- and solubility-enhancingmodifications.” Journal of Medicinal Chemistry 35 (11): 1239-42, whichis incorporated herein by reference). BQ123 is available commerciallyfrom, e.g., ABI Chem (AC1L9EDH).

In some embodiments, pharmaceutical compositions herein comprise aneffective amount of a specifically deuterated ETBR antagonist incombination with an effective amount of an ETAR antagonist, and apharmaceutically acceptable carrier. In some embodiments, the effectiveamount of an ETAR is a synergistically effective amount. In someembodiments, the specifically deuterated ETBR antagonist is at least oneof a deuterated form of BQ-788, A192621, or a combination thereof,including analogs, derivatives, polymorphs, prodrugs, and salts thereof.In some embodiments, the ETAR antagonist is BQ123, including analogs,derivatives, polymorphs, prodrugs, and salts thereof.

In some embodiments, the additional anti-oncologic agent is at least oneof apx005m, ipilimumab, vemurafenib, dacabazine, nivolumab,pembrolizumab, niacinamide, interleukin-2, DEDN6526, Talimogenelaherparepvec, tumor infiltrating lymphocytes, an anti-angiogenic agent,adriamycin, camptothecin, carboplatin, cisplatin, daunorubicin,doxorubicin, alpha, beta, or gamma interferon, irinotecan, docetaxel,paclitaxel, topotecan, atrasentan, tezosentan, bosentan, sitaxsentan,enrasentan, zibotentan, Ro468443, TBC10950, TBC10894, A192621, A308165,SB209670, SB17242, A182086, (s)-Lu302872, J-104132, TAK-044, Sarafotoxin56c, IRL2500, RES7011, Aselacins A, B, and C, Ro470203, Ro462005,sulfamethoxazole, cochinmicin I, II, and III, L749329, L571281, L754142,J104132, CGS27830, PD142893, PD143296, PD145065, PD156252, PD159020,PD160672, PD160874, TM-ET-1, IRL3630, Ro485695, L75037, LU224332,PD142893, LU302872, PD145065, Ro610612, SB217242, or a combinationsthereof. In some embodiments, the additional anti-oncologic agent is aRAF kinase antagonist, a MEK antagonist or a combination thereof. Insome embodiments, the anti-oncologic agent is at least one of an IDOinhibitor, HDAC inhibitor, DNMT inhibitor, adenosine receptor inhibitor,CXCR4/CXCL12 axis inhibitor or a combination thereof. In someembodiments, the DNMT inhibitor is vidaza. In some embodiments, the HDACinhibitor is at least one of entinostat, mocetinostat, inostat,romidepsin, ACY-241, farydak or a combination thereof. In someembodiments, the adenosine receptor inhibitor is at least one of CPI-444(V81444), PBF-509, MEDI9447, MK-3814, AZD4635, BMS-986179 or acombination thereof. In some embodiments, the CXCR4/CXCL12 axisinhibitor is at least one of ulocuplumab, BL-8040, PF-06747143, POL6326,plerixafor, ALX-0651, LY2510924, AMD11070, X4P-001, Q122, USL311,burixafor hyrobromid, CX-01, CTCE 9908, GMI-1359 or a combinationthereof. In some embodiments, the anti-oncologic agent is ananti-angiogenic agent selected from thalidomide, marimastat, COL-3,BMS275291, squalamine, 2-ME, SU6668, neovastat, Medi522, EMD121974, CAI,celecoxib, interleukin-12, IM862, TNP470, avastin, gleevac, herceptin,or a combination thereof. In some embodiments, the anti-oncologic agentis a cell CDK4/6 cycle inhibitor, for example, ribociclib, palbociclib,milciclib, voruciclib, abemaciclib, flavopiridol or a combinationthereof.

In some embodiments, a dosage of the specifically deuterated ETBRantagonist is about 0.1 μg to about 500 mg (e.g., about 100 μg to about4000 μg) and/or a concentration of the specifically deuterated ETBRantagonist is about 0.01 μg/mL to about 1000 mg/mL of the composition(e.g., about 0.1 mg/mL to about 5 mg/mL).

In some embodiments, a dosage of the ETAR antagonist is about 0.1 μg toabout 500 mg (e.g., about 100 μg to about 4000 μg) and/or aconcentration of the ETAR antagonist is about 0.01 μg/mL to about 1000mg/mL of the composition (e.g., about 0.1 mg/mL to about 5 mg/mL).

In some embodiments, a dosage of the anti-PD1 antibody is about 0.1 μgto about 500 mg (e.g., about 100 μg to about 4000 μg) and/or aconcentration of the anti-PD1 antibody is about 0.01 μg/mL to about 1000mg/mL of the composition (e.g., about 0.1 mg/mL to about 5 mg/mL).

In some embodiments, a dosage of the bRAF inhibitor is about 0.1 μg toabout 500 mg (e.g., about 100 μg to about 4000 μg) and/or aconcentration of the bRAF inhibitor is about 0.01 μg/mL to about 1000mg/mL of the composition (e.g., about 0.1 mg/mL to about 5 mg/mL).

In some embodiments, a dosage of the niacinamide is about 0.1 μg toabout 500 mg (e.g., about 100 μg to about 4000 μg) and/or aconcentration of the niacinamide is about 0.01 μg/mL to about 1000 mg/mLof the composition (e.g., about 0.1 mg/mL to about 5 mg/mL).

In some embodiments, a dosage of the caspase-8 inhibitor is about 0.1 μgto about 500 mg (e.g., about 100 μg to about 4000 μg or about 1 μg toabout 4000 μg) and/or a concentration of the caspase-8 inhibitor isabout 0.01 μg/mL to about 1000 mg/mL of the composition (e.g., about 0.1mg/mL to about 5 mg/mL).

In some embodiments, the concentration of the at least one specificallydeuterated ETBR antagonist, and/or the at least one anti-oncologic agentcan independently be about 0.01 μg/mL to about 1000 mg/mL, about 0.01μg/mL to about 750 mg/mL, about 0.01 μg/mL to about 500 mg/mL, about0.01 μg/mL to about 300 mg/mL, about 0.01 μg/mL to about 150 mg/mL,about 0.01 μg/mL to about 100 mg/mL, about 0.01 μg/mL to about 50 mg/mL,about 0.01 μg/mL to about 25 mg/mL, about 0.01 μg/mL to about 10 mg/mL,about 0.01 μg/mL to about 1.0 mg/mL, about 0.01 μg/mL to about 0.1μg/mL, about 0.1 μg/mL to about 750 mg/mL, about 0.1 μg/mL to about 500mg/mL, about 0.1 μg/mL to about 300 mg/mL, about 0.1 μg/mL to about 150mg/mL, about 0.1 μg/mL to about 100 mg/mL, about 0.1 μg/mL to about 50mg/mL, about 0.1 μg/mL to about 25 mg/mL, about 0.1 μg/mL to about 10mg/mL, about 0.1 μg/mL to about 1.0 mg/mL, about 1.0 μg/mL to about 750mg/mL, about 1.0 μg/mL to about 500 mg/mL, about 1.0 μg/mL to about 300mg/mL, about 1.0 μg/mL to about 150 mg/mL, about 1.0 μg/mL to about 100mg/mL, about 1.0 μg/mL to about 50 mg/mL, about 1.0 μg/mL to about 25mg/mL, about 1.0 μg/mL to about 10 mg/mL, about 10 μg/mL to about 750mg/mL, about 10 μg/mL to about 500 mg/mL, about 10 μg/mL to about 300mg/mL, about 10 μg/mL to about 150 mg/mL, about 10 μg/mL to about 100mg/mL, about 10 μg/mL to about 50 mg/mL, about 10 μg/mL to about 25mg/mL, about 25 μg/mL to about 750 mg/mL, about 25 μg/mL to about 500mg/mL, about 25 μg/mL to about 300 mg/mL, about 25 μg/mL to about 150mg/mL, about 25 μg/mL to about 100 mg/mL, about 25 μg/mL to about 50mg/mL, about 50 μg/mL to about 750 mg/mL, about 50 μg/mL to about 500mg/mL, about 50 μg/mL to about 300 mg/mL, about 50 μg/mL to about 150mg/mL, about 50 μg/mL to about 100 mg/mL, about 100 μg/mL to about 750mg/mL, about 100 μg/mL to about 500 mg/mL, about 100 μg/mL to about 300mg/mL, about 100 μg/mL to about 150 mg/mL, about 150 μg/mL to about 750mg/mL, about 150 μg/mL to about 500 mg/mL, about 150 μg/mL to about 300mg/mL, about 300 μg/mL to about 750 mg/mL, about 300 μg/mL to about 500mg/mL, or about 500 μg/mL to about 750 mg/mL.

In some embodiments, the dosage of the at least one specificallydeuterated ETBR antagonist, and/or at least one anti-oncologic agent canindependently be about 0.1 μg to about 5000 μg, about 0.1 μg to about4500 μg, about 0.1 μg to about 4000 μg, about 0.1 μg to about 3500 μg,about 0.1 μg to about 3000 μg, about 0.1 μg to about 2500 μg, about 0.1μg to about 2000 μg, about 0.1 μg to about 1500 μg, about 0.1 μg toabout 1000 μg, about 0.1 μg to about 500 μg, about 1.0 μg to about 5000μg, about 1.0 μg to about 4500 μg, about 1.0 μg to about 4000 μg, about1.0 μg to about 3500 μg, about 1.0 μg to about 3000 μg, about 1.0 μg toabout 2500 μg, about 1.0 μg to about 2000 μg, about 1.0 μg to about 1500μg, about 1.0 g to about 1000 μg, about 1.0 μg to about 500 μg, about100 μg to about 5000 μg, about 100 μg to about 4500 μg, about 100 μg toabout 4000 μg, about 100 μg to about 3500 μg, about 100 μg to about 3000μg, about 100 μg to about 2500 μg, about 100 μg to about 2000 μg, about100 μg to about 1500 μg, about 100 μg to about 1000 μg, about 100 μg toabout 500 μg, about 250 μg to about 5000 μg, about 250 μg to about 4500μg, about 250 μg to about 4000 μg, about 250 μg to about 3500 μg, about250 μg to about 3000 μg, about 250 μg to about 2500 μg, about 250 μg toabout 2000 μg, about 250 μg to about 1500 μg, about 250 μg to about 1000μg, about 250 μg to about 500 μg, about 500 μg to about 5000 μg, about500 μg to about 4500 μg, about 500 μg to about 4000 μg, about 500 μg toabout 3500 μg, about 500 μg to about 3000 μg, about 500 μg to about 2500μg, about 500 μg to about 2000 μg, about 500 μg to about 1500 μg, about500 μg to about 1000 μg, about 750 μg to about 5000 μg, about 750 μg toabout 4500 μg, about 750 μg to about 4000 μg, about 750 μg to about 3500μg, about 750 μg to about 3000 μg, about 750 μg to about 2500 μg, about750 μg to about 2000 μg, about 75 μg to about 1500 μg, about 750 μg toabout 1000 μg, about 1500 μg to about 5000 μg, about 1500 μg to about4500 μg, about 1500 μg to about 4000 μg, about 1500 μg to about 3500 μg,about 1500 μg to about 3000 μg, about 1500 μg to about 2500 μg, about1500 μg to about 2000 μg, about 2000 μg to about 5000 μg, about 2000 μgto about 4500 μg, about 2000 μg to about 4000 μg, about 2000 μg to about3500 μg, about 2000 μg to about 3000 μg, about 2000 μg to about 2500 μg,about 2500 μg to about 5000 μg, about 2500 μg to about 4500 μg, about2500 μg to about 4000 μg, about 2500 μg to about 3500 μg, about 2500 μgto about 3000 μg, about 3000 μg to about 5000 μg, about 3000 μg to about4500 μg, about 3500 μg to about 4000 μg, about 3500 μg to about 5000 μg,about 3500 μg to about 4500 μg, about 3500 μg to about 4000 μg, about4000 μg to about 5000 μg, about 4000 μg to about 4500 μg, or about 4500μg to about 5000 μg.

In some embodiments, a dosage of the anti-PD1 antibody is about 0.1mg/kg to about 9.0 mg/kg. For example, the dosage of the anti-PD1antibody is about 0.1 mg/kg to about 9.0 mg/kg, about 0.1 mg/kg to about8.0 mg/kg, about 0.1 mg/kg to about 7.0 mg/kg, about 0.1 mg/kg to about6.0 mg/kg, about 0.1 mg/kg to about 5.0 mg/kg, about 0.1 mg/kg to about4.0 mg/kg, about 0.1 mg/kg to about 3.0 mg/kg, about 0.1 mg/kg to about2.0 mg/kg, about 0.1 mg/kg to about 1.0 mg/kg, about 1.0 mg/kg to about9.0 mg/kg, about 1.0 mg/kg to about 8.0 mg/kg, about 1.0 mg/kg to about7.0 mg/kg, about 1.0 mg/kg to about 6.0 mg/kg, about 1.0 mg/kg to about5.0 mg/kg, about 1.0 mg/kg to about 4.0 mg/kg, about 1.0 mg/kg to about3.0 mg/kg, about 1.0 mg/kg to about 2.0 mg/kg, about 2.0 mg/kg to about9.0 mg/kg, about 2.0 mg/kg to about 8.0 mg/kg, about 2.0 mg/kg to about7.0 mg/kg, about 2.0 mg/kg to about 6.0 mg/kg, about 2.0 mg/kg to about5.0 mg/kg, about 2.0 mg/kg to about 4.0 mg/kg, about 2.0 mg/kg to about3.0 mg/kg, about 3.0 mg/kg to about 9.0 mg/kg, about 3.0 mg/kg to about8.0 mg/kg, about 3.0 mg/kg to about 7.0 mg/kg, about 3.0 mg/kg to about6.0 mg/kg, about 3.0 mg/kg to about 5.0 mg/kg, about 3.0 mg/kg to about4.0 mg/kg, about 4.0 mg/kg to about 9.0 mg/kg, about 4.0 mg/kg to about8.0 mg/kg, about 4.0 mg/kg to about 7.0 mg/kg, about 4.0 mg/kg to about6.0 mg/kg, about 4.0 mg/kg to about 5.0 mg/kg, about 5.0 mg/kg to about9.0 mg/kg, about 5.0 mg/kg to about 8.0 mg/kg, about 5.0 mg/kg to about7.0 mg/kg, about 5.0 mg/kg to about 6.0 mg/kg, about 6.0 mg/kg to about9.0 mg/kg, about 6.0 mg/kg to about 8.0 mg/kg, about 6.0 mg/kg to about7.0 mg/kg, about 7.0 mg/kg to about 9.0 mg/kg, about 7.0 mg/kg to about8.0 mg/kg, or about 8.0 mg/kg to about 9.0 mg/kg.

In some embodiments, a dosage of the bRAF inhibitor is about 1 mg toabout 1500 mg. For example, the dosage of the bRAF inhibitor about 1 mgto about 1500 mg, about 1 mg to about 1250 mg, about 1 mg to about 1000mg, about 1 mg to about 750 mg, about 1 mg to about 500 mg, about 1 mgto about 250 mg, about 250 mg to about 1500 mg, about 250 mg to about1250 mg, about 250 mg to about 1000 mg, about 250 mg to about 750 mg,about 250 mg to about 500 mg, about 500 mg to about 1500 mg, about 500mg to about 1250 mg, about 500 mg to about 1000 mg, about 500 mg toabout 750 mg, about 750 mg to about 1500 mg, about 750 mg to about 1250mg, about 750 mg to about 1000 mg, about 1000 mg to about 1500 mg, about1000 mg to about 1250 mg, or about 1250 mg to about 1500 mg.

In some embodiments, a dosage of the niacinamide is about 1 mg to about3000 mg. For example, the dosage of the niacinamide is about 1 mg toabout 3000 mg, about 1 mg to about 2750 mg, about 1 mg to about 2500 mg,about 1 mg to about 2250 mg, about 1 mg to about 2000 mg, about 1 mg toabout 1750 mg, about 1 mg to about 1500 mg, about 1 mg to about 1250 mg,about 1 mg to about 1000 mg, about 1 mg to about 750 mg, about 1 mg toabout 500 mg, about 1 mg to about 250 mg, about 250 mg to about 3000 mg,about 250 mg to about 2750 mg, about 250 mg to about 2500 mg, about 250mg to about 2250 mg, about 250 mg to about 2000 mg, about 250 mg toabout 1750 mg, about 250 mg to about 1500 mg, about 250 mg to about 1250mg, about 250 mg to about 1000 mg, about 250 mg to about 750 mg, about250 mg to about 500 mg, about 500 mg to about 3000 mg, about 500 mg toabout 2750 mg, about 500 mg to about 2500 mg, about 500 mg to about 2250mg, about 500 mg to about 2000 mg, about 500 mg to about 1750 mg, about500 mg to about 1500 mg, about 500 mg to about 1250 mg, about 500 mg toabout 1000 mg, about 500 mg to about 750 mg, about 750 mg to about 3000mg, about 750 mg to about 2750 mg, about 750 mg to about 2500 mg, about750 mg to about 2250 mg, about 750 mg to about 2000 mg, about 750 mg toabout 1750 mg, about 750 mg to about 1500 mg, about 750 mg to about 1250mg, about 750 mg to about 1000 mg, about 1000 mg to about 3000 mg, about1000 mg to about 2750 mg, about 1000 mg to about 2500 mg, about 1000 mgto about 2250 mg, about 1000 mg to about 2000 mg, about 1000 mg to about1750 mg, about 1000 mg to about 1500 mg, about 100 mg to about 1250 mg,about 1250 mg to about 3000 mg, about 1250 mg to about 2750 mg, about1250 mg to about 2500 mg, about 1250 mg to about 2250 mg, about 1250 mgto about 2000 mg, about 1250 mg to about 1750 mg, about 1250 mg to about1500 mg, about 1500 mg to about 3000 mg, about 1500 mg to about 2750 mg,about 1500 mg to about 2500 mg, about 1500 mg to about 2250 mg, about1500 mg to about 2000 mg, about 1500 mg to about 1750 mg, about 1750 mgto about 3000 mg, about 1750 mg to about 2750 mg, about 1750 mg to about2500 mg, about 1750 mg to about 2250 mg, about 1750 mg to about 2000 mg,about 2000 mg to about 3000 mg, about 2000 mg to about 2750 mg, about2000 mg to about 2500 mg, about 2000 mg to about 2250 mg, about 2250 mgto about 3000 mg, about 2250 mg to about 2750 mg, about 2250 mg to about2500 mg, about 2500 mg to about 3000 mg, about 2500 mg to about 2750 mg,or about 2750 mg to about 3000 mg.

Kits

Disclosed herein is a kit or pharmaceutical compositions for treatmentof a solid tumor cancer in a subject, e.g., a human subject, comprisingat least one ETBR antagonist in an amount effective for use in acombination therapy with at least one immune checkpoint inhibitor, and apharmaceutically acceptable carrier. In some embodiments, the at leastone ETBR antagonist is at least one specifically deuterated ETBRantagonist, e.g., deuterated BQ-788 as described herein. In someembodiments, the at least one ETBR antagonist, e.g., deuterated BQ-788,is disposed in a single container with the immune checkpoint inhibitor.In some embodiments, the at least one ETBR antagonist, e.g., deuteratedBQ-788, is disposed in a first container, and the immune checkpointinhibitor is disposed in a second container, wherein the at least oneETBR antagonist and the immune checkpoint inhibitor are to beadministered approximately contemporaneously.

In some embodiments, the description provides a kit for treatment of asolid tumor cancer in a human subject, comprising an amount of at leastone immune checkpoint inhibitor, a synergistically effective amount ofBQ-788, and a pharmaceutically acceptable carrier or excipient. In someembodiments, the BQ-788 is at least one deuterated BQ-788. In someembodiments, the at least one checkpoint inhibitor is an anti-PD1antibody or anti-PD-L1 antibody.

Routes of Administration

Disclosed herein is a variety of routes of administration for thepharmaceutical compositions disclosed herein. The compounds as describedherein may, in accordance with the disclosure, be administered in singleor divided doses by the oral, parenteral or topical routes.Administration of the active compound may range from continuous(intravenous drip) to several oral administrations per day (for example,Q.O.D. or Q.I.D.) and may include oral, topical, parenteral,intramuscular, intravenous, sub-cutaneous, transdermal (which mayinclude a penetration enhancement agent), buccal, sublingual andsuppository administration, among other routes of administration.Enteric coated oral tablets may also be used to enhance bioavailabilityof the compounds from an oral route of administration. The mosteffective dosage form will depend upon the pharmacokinetics of theparticular agent(s) chosen as well as the severity of disease in thepatient. Administration of compounds according to the present disclosureas sprays, mists, or aerosols for intra-nasal, intra-tracheal orpulmonary administration may also be used. The present disclosuretherefore also is directed to pharmaceutical compositions comprising aneffective amount of compound as described herein, optionally incombination with a pharmaceutically acceptable carrier, additive orexcipient. Compounds according to the present disclosure may beadministered in immediate release, intermediate release or sustained orcontrolled release forms. In some embodiments, sustained or controlledrelease forms are y administered orally, but also in suppository andtransdermal or other topical forms. Intramuscular injections inliposomal form may also be used to control or sustain the release ofcompound at an injection site.

In some embodiments, the pharmaceutical compositions as described hereinis administered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. In some embodiments, the compositions areadministered orally, intraperitoneally or intravenously.

In some embodiments, sterile injectable forms of the compositions asdescribed herein are aqueous or oleaginous suspension. These suspensionsmay be formulated using suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1, 3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil, castor oil or soybean oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

In some embodiments, the pharmaceutical compositions as described hereinare orally administered in any orally acceptable dosage form including,but not limited to, capsules, tablets, aqueous suspensions or solutions.In the case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions are used orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

In some embodiments, the pharmaceutical compositions as described hereinare administered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient, which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

In some embodiments, the pharmaceutical compositions as described hereinare administered topically. Suitable topical formulations are readilyprepared for each of these areas or organs. Topical application for thelower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-acceptable transdermal patches may also be used.

In some embodiments, for topical applications, the pharmaceuticalcompositions are formulated in a suitable ointment containing the activecomponent suspended or dissolved in one or more carriers. Carriers fortopical administration of the compounds of this disclosure include, butare not limited to, mineral oil, liquid petrolatum, DMSO, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. In some embodiments, the compoundsmay be coated onto a stent which is to be surgically implanted into apatient in order to inhibit or reduce the likelihood of occlusionoccurring in the stent in the patient.

In some embodiments, the pharmaceutical compositions are formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

In some embodiments, for ophthalmic use, the pharmaceutical compositionsare formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or as solutions in isotonic, pH adjusted sterile saline,either with or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

In some embodiments, the pharmaceutical compositions as described hereinare administered by nasal aerosol or inhalation. Such compositions areprepared according to techniques described herein relating topharmaceutical compositions and may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents. In some embodiments, thedescription provides formulations comprising liposomes including aneffective amount (e.g., a synergistically effective amount) of at leastone of a ETBR antagonist or a caspase-8 inhibitor or a combinationthereof, and/or an effective amount (e.g., a synergistically effectiveamount) of at least one of an ETAR antagonist, an anti-PD1 antibody, abRAF inhibitor, niacinamide or a combination thereof, wherein theliposome formulation is configured or adapted for intranasal delivery orsublingual delivery. In a further embodiment, the liposomes furthercomprise an additional anti-cancer agent as described above.

In some embodiments, the compositions should be formulated to containbetween about 0.05 milligram to about 750 milligrams or more, forexample about 1 milligram to about 600 milligrams, or about 10milligrams to about 500 milligrams of active ingredient, alone or incombination with at least one other compound according to the presentdisclosure. It should also be understood that a specific dosage andtreatment regimen for any particular patient will depend upon a varietyof factors, including the activity of the specific compound employed,the age, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

In some embodiments, a patient or subject in need of therapy usingcompounds according to the methods described herein is treated byadministering to the patient (subject) an effective amount of thecompound according to the present disclosure including pharmaceuticallyacceptable salts, solvates or polymorphs thereof optionally in apharmaceutically acceptable carrier or diluent, either alone, or incombination with other known erythopoiesis stimulating agents asotherwise identified herein.

In some embodiments, the compounds or compositions herein areadministered orally, parenterally, intradermally, by an injection(intravenously, subcutaneously, or intramuscularly), topically,including transdermally, in liquid, cream, gel, or solid form, or byaerosol form.

In some embodiments, the active ingredients are included in thepharmaceutically acceptable carrier or diluent in an amount sufficientto deliver to a patient a therapeutically effective amount for thedesired indication, without causing serious toxic effects in the patienttreated. An exemplary dose of the active compound for all of theherein-mentioned conditions is in the range from about 10 ng/kg to 300ng/kg, about 10 ng/kg to 1 μg/kg, about 1 μg/kg to 10 μg/kg, about 10μg/kg to 100 μg/kg, about 100 μg/kg to 1000 μg/kg, about 1 mg/kg to 30mg/kg, about 1 mg/kg to 300 mg/kg, or 0.1 to 100 mg/kg per day, moregenerally 0.5 to about 25 mg per kilogram body weight of therecipient/patient per day. A typical topical dosage will range from0.01-5% wt/wt in a suitable carrier.

In some embodiments, the active ingredient herein is convenientlyadministered in any suitable unit dosage form, including but not limitedto, one containing less than 1 mg, 1 mg to 3000 mg, for example 5 to 500mg of active ingredient per unit dosage form. An oral dosage of about25-250 mg is often convenient.

In some embodiments, the active ingredient is administered to achievepeak plasma concentrations of the active compound of about 0.00001-30mM, for example about 0.1-30 M. This may be achieved, for example, bythe intravenous injection of a solution or formulation of the activeingredient, optionally in saline, or an aqueous medium or administeredas a bolus of the active ingredient. Oral administration is alsoappropriate to generate effective plasma concentrations of active agent.

Methods for Treatment

Disclosed herein are methods for treating or ameliorating a disease,disorder or symptom thereof in a subject or a patient, e.g., an animalsuch as a human, comprising administering to a subject in need thereofan effective amount, e.g., a therapeutically effective amount or asynergistically effective amount, of a pharmaceutical composition asdescribed herein, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.In some embodiments, the disease or disorder is an ETBR-related canceror a cancer that is insensitive to immune based therapy or both. In someembodiments, the pharmaceutical composition comprises an effectiveamount of a specifically deuterated ETBR antagonist, e.g., deuteratedBQ-788 or BQ-788-B, as described herein. In some embodiments, theETBR-related cancer is at least one of breast cancer, metastatic breastcancer, melanoma, squamous cell carcinoma, glioblastoma or a combinationthereof. In some embodiments, the cancer is a solid tumor cancer. Insome embodiments, the ETBR-related cancer to be treated does not includebreast cancer, melanoma, metastatic breast cancer or metastaticmelanoma.

In some embodiments, the administration of a specifically deuteratedETBR antagonist alone or in a combination with administration of atleast one ETBR antagonist and an immune checkpoint inhibitor issufficient to effectuate the treatment or amelioration of at least onesymptom of cancer. In some embodiments, administration of the ETBRantagonist alone or in a combination with immune checkpoint inhibitoreffectuates stimulation or enhancement of tumor infiltratinglymphocytes, macrophages, tertiary lymphoid organ formation or acombination thereof. In some embodiments, treatment or amelioration ofcancer or stimulation or enhancement of tumor infiltrating lymphocytes,macrophages, induce tertiary lymphoid organ formation or a combinationthereof, as determined using a V600E+SM1 cancer model in mice, e.g.,C57BL/6 mouse model. In some embodiments, the at least one ETBRantagonist and immune checkpoint inhibitor (whether in singleformulation or separate) are administered in unit dosage forms. In someembodiments, the unit dosage form or forms comprises a synergisticallyeffective amount of each of the at least one ETBR antagonist, and theimmune checkpoint inhibitor.

In some embodiments, the description provides methods for treatingcancer in a subject, e.g., a solid tumor cancer, comprisingadministering to a subject in need thereof an effective dose of aspecifically deuterated ETBR antagonist as described herein alone or ina combination with an immune checkpoint inhibitor, wherein theadministering effectuates the treatment or amelioration of at least onesymptom of the cancer.

In some embodiments, the description provides methods of treating cancerin a subject comprising administering to a subject in need thereof aneffective dose of a specifically deuterated ETBR antagonist as describedherein, and administering to the subject an immune checkpoint inhibitor,wherein the administrations effectuate at least one of:

a. enhancement or stimulation of tumor infiltrating lymphocytes (TILs),

b. increased tumor associated macrophages (TAMs),

c. enhancement or stimulation of tertiary lymphoid organ (TLO) formationor

d. a combination thereof, and

thereby treating or ameliorating at least one symptom of the cancer. Insome embodiments, (a)-(d) are determined in a human by biopsy or in ananimal model. In some embodiments, the animal model is a V600E+SM1cancer model in mice, e.g., C57BL/6 mouse model.

In some embodiments, the at least one specifically deuterated ETBRantagonist is at least one deuterated form of BQ-788 as describedherein. In further embodiments, the deuterated BQ-788 is BQ-788-A,BQ-788-B, BQ-788-C or a combination thereof.

In some embodiments, a method for treating cancer herein comprisesadministering to a patient in need thereof at least one ETBR antagonist,wherein the at least one ETBR antagonist is effective in treating orameliorating at least one symptom of the cancer in the patient. In someembodiments, the at least one ETBR antagonist is at least onespecifically deuterated ETBR antagonist. In some embodiments, the methodcomprises administering an effective amount of the at least onespecifically deuterated ETBR antagonist as described herein, e.g., adeuterated form of BQ-788. In some embodiments, the deuterated BQ-788 isat least one of BQ-788-A, BQ-788-B, or BQ-788-C. In some embodiments,the cancer is an ETBR-related cancer, e.g., an ETBR-related solid tumorcancer. In some embodiments, the ETBR-related cancer is at least one ofbreast cancer, melanoma, squamous cell carcinoma, glioblastoma, ovariancancer, pancreatic cancer or a combination thereof. In some embodiments,the cancer is a solid tumor cancer. In further embodiments, the canceris not breast cancer, melanoma, metastatic breast cancer or metastaticmelanoma.

In some embodiments, the method comprises administering a compositioncomprising an effective amount of at least one ETBR antagonist, e.g., atleast one specifically deuterated ETBR antagonist as described herein,and a pharmaceutically acceptable carrier or excipient as describedherein. In some embodiments, the composition is administered in unitdosage form.

In some embodiments, the method further comprises administering anadditional anti-oncologic agent in combination with, e.g., either in thesame or separate formulations, a specifically deuterated ETBR antagonistsuch as a deuterated BQ-788, as described herein. In some embodiments,the anti-oncologic agent is an anti-PD1 antibody or anti-PD-L1 antibody.In some embodiments, the anti-oncologic agent, e.g., anti-PD1 oranti-PD-L1 antibody is administered as a composition comprising apharmaceutically acceptable carrier or excipient.

In some embodiments, the method comprises administering a combinationcomprising at least one specifically deuterated ETBR antagonist asdescribed herein, and at least one additional anti-oncologic agent asdescribed herein. In some embodiments, the combination comprises apharmaceutically acceptable carrier or excipient. In some embodiments,the combination comprises an effective amount of at least onespecifically deuterated ETBR antagonist, e.g., a deuterated BQ-788, asdescribed herein. In some embodiments, the combination comprises anamount of an immune checkpoint inhibitor and a synergistically effectiveamount of the at least one specifically deuterated ETBR antagonist, suchas a deuterated BQ-788. In some embodiments, the immune checkpointinhibitor is an anti-PD1 antibody.

In some embodiments, the combination comprises an effective amount of aspecifically deuterated ETBR antagonist as described herein, and asynergistically effective amount of the at least one anti-oncologicagent. In some embodiments, the combination includes a pharmaceuticalacceptable carrier. In some embodiments, the combination is comprisedwithin one or more unit dosage forms. In further embodiments, thecombination is administered in separate unit dosage forms, for example,a first container comprising the at least one ETBR antagonist, and asecond container comprising the at least one anti-oncologic agent, suchas an immune checkpoint inhibitor. In some embodiments, the specificallydeuterated ETBR antagonist is a deuterated BQ-788 as described herein.

In some embodiments, the pharmaceutical compositions are deliveredintravenously, intramuscularly, subcutaneously, orally, intranasally,sublingually, transdermally, topically, intraperitoneally, parenterally,intranasally, or intracranially.

In some embodiments, the ETBR-antagonist, e.g., deuteratedETBR-antagonist or deuterated BQ-788, is administered in the form of aliposomal formulation as described herein.

In some embodiments, a method for treating ETBR-related metastatic braincancer is provided. The method comprises administering an effectiveamount to a subject in need thereof a pharmaceutical composition of thepresent disclosure, wherein the pharmaceutical composition is effectivefor treating or ameliorating a symptom of ETBR-related metastatic braincancer. In some embodiments, the ETBR-related metastatic brain cancer ismetastatic melanoma-related brain cancer, metastatic squamous cellcarcinoma-related brain cancer, glioblastoma or a combination thereof.In some embodiments, the composition comprises an effective amount of aspecifically deuterated ETBR antagonist, e.g., a deuterated BQ-788 asdescribed herein, and a pharmaceutically acceptable carrier.

In some embodiments, the description provides methods for treating asolid tumor cancer in a human subject, comprising administeringeffective doses of an ETBR antagonist and further administering animmune checkpoint inhibitor to the subject in need thereof, wherein theadministration of the ETBR antagonist and immune checkpoint inhibitoreffectuates at least one of: (i) enhancement or stimulation of tumorinfiltrating lymphocytes (TILs), (ii) increased tumor associatedmacrophages (TAMs), (iii) enhancement or stimulation of tertiarylymphoid organ (TLO) formation or (iv) a combination thereof, whereinthe ETBR antagonist and immune checkpoint inhibitor effectuate thetreatment or alleviation of at least one symptom of the solid tumorcancer. In some embodiments, the formation of (i)-(iv) is performed in amouse model. In some embodiments, the mouse model is the V600E+SM1cancer model in C57BL/6 mice. In some embodiments, the immune checkpointinhibitor is an anti-PD1 or anti-PD-L1 antibody. In some embodiments,the effective dose is a synergistically effective amount, e.g., from 0.1μg to 5000 mg. In some embodiments, the specifically deuterated ETBRantagonist is a deuterated BQ-788. In some embodiments, the deuteratedBQ-788 is BQ-788-B. In some embodiments, the specifically deuteratedETBR antagonist, e.g., deuterated BQ-788, includes a pharmaceuticallyacceptable carrier or excipient. In some embodiments, the ETBRantagonist (e.g., deuterated ETBR such as deuterated BQ-788) and immunecheckpoint inhibitor are administered separately. In some embodiments,the ETBR antagonist (e.g., deuterated ETBR such as deuterated BQ-788)and immune checkpoint inhibitor are administered in the sameformulation.

In some embodiments, the description provides a method of treating anETBR-related solid tumor cancer in a subject comprising administering toa subject in need thereof, e.g., a human, at least one deuterated BQ-788at an effective amount or synergistically effective amount with animmune checkpoint inhibitor, and a pharmaceutically acceptable carrieror excipient, wherein the deuterated BQ-788 and immune checkpointinhibitor effectuate the treatment or amelioration of at least onesymptom of the ETBR-related solid tumor cancer in the subject. In someembodiments, the deuterated BQ-788 is administered as a liposomalformulation.

In some embodiments, the immune based therapy includes at least one ofan immune checkpoint inhibitor (e.g., an anti-PD-1 antibody), a cancervaccine, a Chimeric Antigen Receptor T-Cell (CAR-T) therapy or acombination thereof.

In some embodiments, the description provides a method of inhibitingmelanoma invasion and metastasis in a patient comprising administeringto a subject in need thereof an effective amount, e.g., atherapeutically effective amount or a synergistically effective amount,of a pharmaceutical composition as described herein, wherein thecomposition is effective for inhibiting melanoma invasion andmetastasis.

In some embodiments, the description provides a method of inducingmelanoma cell death (apoptosis) comprising administering to a subject inneed thereof an effective amount, e.g., a therapeutically effectiveamount or a synergistically effective amount, of a pharmaceuticalcomposition as described herein, wherein the composition is effectivefor inducing melanoma cell death.

In some embodiments, the description provides a method of inhibitingblood supply to melanoma tumors in a patient comprising administering toa subject in need thereof an effective amount, e.g., a therapeuticallyeffective amount or a synergistically effective amount, of apharmaceutical composition as described herein, wherein the compositionis effective for inhibiting blood supply to melanoma tumors.

In some embodiments, the pharmaceutical composition comprises about 1%to about 95% of the active ingredient, single-dose forms ofadministration comprising about 20% to about 90% of the activeingredient and administration forms which are not single-dose comprisingabout 5% to about 20% of the active ingredient. Unit dose forms are, forexample, coated tablets, tablets, ampoules, vials, suppositories orcapsules. Other forms of administration are, for example, ointments,creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersionsand the like. Examples are capsules containing from about 0.05 g toabout 1.0 g of the active ingredient.

In some embodiments, the active ingredient is included in thepharmaceutically acceptable carrier or diluent in an amount sufficientto deliver to a patient a therapeutically effective amount for thedesired indication, without causing serious toxic effects in the patienttreated. An exemplary dose of the active compound for all of theherein-mentioned conditions is in the range from about 10 ng/kg to 300mg/kg, for example 0.1 to 100 mg/kg per day, more generally 0.5 to about25 mg per kilogram body weight of the recipient/patient per day. Atypical topical dosage will range from 0.01-5% wt/wt in a suitablecarrier. The compound is conveniently administered in any suitable unitdosage form, including but not limited to one containing less than 1 mg,1 mg to 3000 mg, for example 5 to 500 mg of active ingredient per unitdosage form. An oral dosage of about 25-250 mg is often convenient. Insome embodiments, the active ingredient is administered to achieve peakplasma concentrations of the active compound of about 0.00001-30 mM, forexample about 0.1-30 M.

Dosage Regimen

Disclosed herein is a treatment regimen. In some embodiments, thetreatment regimen includes a dosage pharmaceutical composition withabout 100 μg to about 4000 μg of each included active ingredient (i.e.,at least one specifically deuterated ETBR antagonist as describedherein, the ETAR antagonist, the anti-PD1 antibody, the bRAF inhibitor,the niacinamide, or the caspase-8 inhibitor). The dosage can be asustained release dosage in which about 50 μg to about 3000 μg of eachof the active ingredients is an initial burst, while about 50 μg toabout 3000 μg of the each of the active ingredients is a sustainedrelease over 2 hours.

In some embodiments, each of the active ingredient of a pharmaceuticalcomposition of the present disclosure can be present in any of thedosage formulation (e.g., initial burst, sustained release dosage, etc.)in about 100 μg to about 4000 μg, about 100 μg to about 3750 μg, about100 μg to about 3500 μg, about 100 μg to about 3250 μg, about 100 μg toabout 3000 μg, about 100 μg to about 2750 μg, about 100 μg to about 2500μg, about 100 μg to about 2250 μg, about 100 μg to about 2000 μg, about100 μg to about 1750 μg, about 100 μg to about 1500 μg, about 100 μg toabout 1250 μg, about 100 μg to about 1000 μg, about 100 μg to about 750μg, about 100 μg to about 500 μg, about 250 μg to about 4000 μg, about250 μg to about 3750 μg, about 250 μg to about 3500 μg, about 250 μg toabout 3250 μg, about 250 μg to about 3000 μg, about 250 μg to about 2750μg, about 250 μg to about 2500 μg, about 250 μg to about 2250 μg, about250 μg to about 2000 μg, about 250 μg to about 1750 μg, about 250 μg toabout 1500 μg, about 250 μg to about 1250 μg, about 250 μg to about 1000μg, about 250 μg to about 750 μg, about 250 μg to about 500 μg, about500 μg to about 4000 μg, about 500 μg to about 3750 μg, about 500 μg toabout 3500 μg, about 500 g to about 3250 μg, about 500 μg to about 3000μg, about 500 μg to about 2750 μg, about 500 μg to about 2500 μg, about500 μg to about 2250 μg, about 500 μg to about 2000 μg, about 500 μg toabout 1750 μg, about 500 μg to about 1500 μg, about 500 μg to about 1250μg, about 500 μg to about 1000 μg, about 500 μg to about 750 μg, about750 μg to about 4000 μg, about 750 μg to about 3750 μg, about 750 μg toabout 3500 μg, about 750 μg to about 3250 μg, about 750 μg to about 3000μg, about 750 μg to about 2750 μg, about 750 μg to about 2500 μg, about750 μg to about 2250 μg, about 750 μg to about 2000 μg, about 750 μg toabout 1750 μg, about 750 μg to about 1500 μg, about 750 μg to about 1250μg, about 750 μg to about 1000 μg, about 1000 μg to about 4000 μg, about1000 μg to about 3750 μg, about 1000 μg to about 3500 μg, about 1000 μgto about 3250 μg, about 1000 μg to about 3000 μg, about 1000 μg to about2750 μg, about 1000 μg to about 2500 μg, about 1000 μg to about 2250 μg,about 1000 μg to about 2000 μg, about 1000 μg to about 1750 μg, about1000 μg to about 1500 μg, about 1000 μg to about 1250 μg, about 1250 μgto about 4000 μg, about 1250 μg to about 3750 μg, about 1250 μg to about3500 μg, about 1250 μg to about 3250 μg, about 1250 μg to about 3000 μg,about 1250 μg to about 2750 μg, about 1250 μg to about 2500 μg, about1250 μg to about 2250 μg, about 1250 μg to about 2000 μg, about 1250 μgto about 1750 μg, about 1250 μg to about 1500 μg, about 1500 μg to about4000 μg, about 1500 μg to about 3750 μg, about 1500 μg to about 3500 μg,about 1500 μg to about 3250 μg, about 1500 μg to about 3000 μg, about1500 μg to about 2750 μg, about 1500 μg to about 2500 μg, about 1500 μgto about 2250 μg, about 1500 μg to about 2000 μg, about 1500 μg to about1750 μg, about 1750 μg to about 4000 μg, about 1750 μg to about 3750 μg,about 1750 μg to about 3500 μg, about 1750 μg to about 3250 μg, about1750 μg to about 3000 μg, about 1750 μg to about 2750 μg, about 1750 μgto about 2500 μg, about 1750 μg to about 2250 μg, about 1750 μg to about2000 μg, about 2000 μg to about 4000 μg, about 2000 μg to about 3750 μg,about 2000 μg to about 3500 μg, about 2000 μg to about 3250 μg, about2000 μg to about 3000 μg, about 2000 μg to about 2750 μg, about 2000 μgto about 2500 μg, about 2000 μg to about 2250 μg, about 2250 μg to about4000 μg, about 2250 μg to about 3750 μg, about 2250 μg to about 3500 μg,about 2250 μg to about 3250 μg, about 2250 μg to about 3000 μg, about2250 μg to about 2750 μg, about 2250 μg to about 2500 μg, about 2500 μgto about 4000 μg, about 2500 μg to about 3750 μg, about 2500 μg to about3500 μg, about 2500 μg to about 3250 μg, about 2500 μg to about 3000 μg,about 2500 μg to about 2750 μg, about 2750 μg to about 4000 μg, about2750 μg to about 3750 μg, about 2750 μg to about 3500 μg, about 2750 μgto about 3250 μg, about 2750 μg to about 3000 μg, about 3000 μg to about4000 μg, about 3000 μg to about 3750 μg, about 3000 μg to about 3500 μg,about 3000 μg to about 3250 μg, about 3250 μg to about 4000 μg, about3250 μg to about 3750 μg, about 3250 μg to about 3500 μg, about 3500 μgto about 4000 μg, about 3500 μg to about 3750 μg, or about 3750 μg toabout 4000 μg.

In some embodiments, each active ingredient of a pharmaceuticalcomposition of the present disclosure is present in about 0.1 mg/mL toabout 50 mg/mL, about 0.1 mg/mL to about 25 mg/mL, about 0.1 mg/mL toabout 10 mg/mL, about 1 mg/mL to about 50 mg/mL, about 1 mg/mL to about25 mg/mL, about 1 mg/mL to about 10 mg/mL, about 0.1 mg/mL to about 5.0mg/mL (e.g., about 0.1 mg/mL to about 4.5 mg/mL, about 0.1 mg/mL toabout 4.0 mg/mL, about 0.1 mg/mL to about 3.5 mg/mL, about 0.1 mg/mL toabout 3.0 mg/mL, about 0.1 mg/mL to about 2.5 mg/mL, about 0.1 mg/mL toabout 2.0 mg/mL, about 0.1 mg/mL to about 1.5 mg/mL, about 0.1 mg/mL toabout 1.0 mg/mL, about 0.1 mg/mL to about 0.5 mg/mL, about 0.5 mg/mL toabout 4.5 mg/mL, about 0.5 mg/mL to about 4.0 mg/mL, about 0.5 mg/mL toabout 3.5 mg/mL, about 0.5 mg/mL to about 3.0 mg/mL, about 0.5 mg/mL toabout 2.5 mg/mL, about 0.5 mg/mL to about 2.0 mg/mL, about 0.5 mg/mL toabout 1.5 mg/mL, about 0.5 mg/mL to about 1.0 mg/mL, about 1.0 mg/mL toabout 4.5 mg/mL, about 1.0 mg/mL to about 4.0 mg/mL, about 1.0 mg/mL toabout 3.5 mg/mL, about 1.0 mg/mL to about 3.0 mg/mL, about 1.0 mg/mL toabout 2.5 mg/mL, about 1.0 mg/mL to about 2.0 mg/mL, about 1.0 mg/mL toabout 1.5 mg/mL, about 1.5 mg/mL to about 4.5 mg/mL, about 1.5 mg/mL toabout 4.0 mg/mL, about 1.5 mg/mL to about 3.5 mg/mL, about 1.5 mg/mL toabout 3.0 mg/mL, about 1.5 mg/mL to about 2.5 mg/mL, about 1.5 mg/mL toabout 2.0 mg/mL, about 2.0 mg/mL to about 4.5 mg/mL, about 2.0 mg/mL toabout 4.0 mg/mL, about 2.0 mg/mL to about 3.5 mg/mL, about 2.0 mg/mL toabout 3.0 mg/mL, about 2.0 mg/mL to about 2.5 mg/mL, about 2.5 mg/mL toabout 4.5 mg/mL, about 2.5 mg/mL to about 4.0 mg/mL, about 2.5 mg/mL toabout 3.5 mg/mL, about 2.5 mg/mL to about 3.0 mg/mL, about 3.0 mg/mL toabout 4.5 mg/mL, about 3.0 mg/mL to about 4.0 mg/mL, about 3.0 mg/mL toabout 3.5 mg/mL, about 3.5 mg/mL to about 4.5 mg/mL, about 3.5 mg/mL toabout 4.0 mg/mL, or about 3.5 mg/mL to about 4.5 mg/mL, relative to thepharmaceutical composition).

In some embodiments, each active ingredient of a pharmaceuticalcomposition of the present disclosure is present in about 0.1 μg/mL toabout 50 μg/mL, about 0.1 μg/mL to about 25 μg/mL, about 0.1 μg/mL toabout 10 μg/mL, about 1 μg/mL to about 50 μg/mL, about 1 μg/mL to about25 μg/mL, about 1 μg/mL to about 10 μg/mL, about 0.1 μg/mL to about 5.0μg/mL, e.g., about 1 μg/mL to about 5 g/mL, about 0.1 μg/mL to about 4.0μg/mL, about 0.1 μg/mL to about 3.5 μg/mL, about 0.1 μg/mL to about 3.0μg/mL, about 0.1 μg/mL to about 2.5 μg/mL, about 0.1 μg/mL to about 2.0μg/mL, about 0.1 μg/mL to about 1.5 μg/mL, about 0.1 μg/mL to about 1.0μg/mL, about 0.1 μg/mL to about 0.5 μg/mL, about 0.5 μg/mL to about 4.5μg/mL, about 0.5 μg/mL to about 4.0 μg/mL, about 0.5 μg/mL to about 3.5μg/mL, about 0.5 μg/mL to about 3.0 μg/mL, about 0.5 μg/mL to about 2.5μg/mL, about 0.5 μg/mL to about 2.0 μg/mL, about 0.5 μg/mL to about 1.5μg/mL, about 0.5 μg/mL to about 1.0 μg/mL, about 1.0 μg/mL to about 4.5μg/mL, about 1.0 μg/mL to about 4.0 μg/mL, about 1.0 μg/mL to about 3.5μg/mL, about 1.0 μg/mL to about 3.0 μg/mL, about 1.0 μg/mL to about 2.5μg/mL, about 1.0 μg/mL to about 2.0 μg/mL, about 1.0 μg/mL to about 1.5μg/mL, about 1.5 μg/mL to about 4.5 μg/mL, about 1.5 μg/mL to about 4.0μg/mL, about 1.5 μg/mL to about 3.5 μg/mL, about 1.5 μg/mL to about 3.0μg/mL, about 1.5 μg/mL to about 2.5 μg/mL, about 1.5 μg/mL to about 2.0μg/mL, about 2.0 μg/mL to about 4.5 μg/mL, about 2.0 μg/mL to about 4.0μg/mL, about 2.0 μg/mL to about 3.5 μg/mL, about 2.0 μg/mL to about 3.0μg/mL, about 2.0 μg/mL to about 2.5 μg/mL, about 2.5 μg/mL to about 4.5μg/mL, about 2.5 μg/mL to about 4.0 μg/mL, about 2.5 μg/mL to about 3.5μg/mL, about 2.5 μg/mL to about 3.0 μg/mL, about 3.0 μg/mL to about 4.5μg/mL, about 3.0 μg/mL to about 4.0 μg/mL, about 3.0 μg/mL to about 3.5μg/mL, about 3.5 μg/mL to about 4.5 μg/mL, about 3.5 μg/mL to about 4.0μg/mL, or about 3.5 μg/mL to about 4.5 μg/mL, relative to thepharmaceutical composition.

EXAMPLES Example 1. Synthesis of Deuterated ETBR Antagonists

Deuterated ETBR antagonists may be prepared by deuterating known andcommercial ETBR antagonists by standard methods and procedures.

Specific deuterated ETBR antagonists may be prepared by the schemespresented below. BQ-788-B can be prepared by the method demonstrated inFIG. 14.

Intermediate 13 of FIG. 14 can be prepared by the following scheme 2depicted in FIG. 15 (Intermediate 13):

A non-deuterated analog of Intermediate 13 can be prepared bysubstituting LiAlH₄ in place of LiAlD₄ in Step 4.

BQ-788-A and BQ-788-C can be prepared by substituting a deuteratedanalog of Intermediate 5 in Step 3 of scheme 1. Such an analog can beprepared by the method demonstrated in FIG. 16 (Intermediate 5d) below:

Compound 10 from Scheme 3 is then used in place of Compound 5 inscheme 1. For BQ-788-C Scheme 1 is then followed to completion. ForBQ-788-A, the non-deuterated analog of Intermediate 13 of Scheme 1 isused Intermediate 4 of Scheme 3 can be prepared by reacting a bromonatedindole with NaBD4 in the presence of a palladium catalyst.

In an exemplary embodiment, compound BQ-788-A can be prepared by themethod demonstrated in FIG. 17.

In addition, compound BQ-788-C can be prepared according to the methoddemonstrated in FIG. 18.

The number and position of the deuterium atoms is not to be limited bythe specific schemes or examples shown herein. The preparation ofcompounds with more deuterium substitution can be readily extrapolatedfrom the schemes presented here using commonly known starting materialsor prepared using standard synthetic methods.

Example 2. Biological Activities of Deuterated ETBR Antagonists

Determination of CXCR4 inhibitory effect. The inhibitory effect on CXCR4(h) was determined for BQ-788 (FIG. 4A), and BQ-788 (FIG. 4B) BQ-788-B(i.e., “Compound 1”). Cellular agonist effect was calculated as a % ofcontrol response to a known reference agonist for CXCR4 (h), andcellular antagonist effect was calculated as a % inhibition of controlreference agonist response for CXCR4. Recombinant human CXCR4 wasexpressed in CHO cells, and stimulated with 1 nM SDF-1α and incubated at28° C. Dielectric spectroscopy was used to measure impedance of thecells. Results showing ≥50% inhibition of agonist effect are consideredsignificant while those showing less than 25% inhibition are notconsidered significant. The IC50 for BQ-788 was greater than about1.0E−6 M. The IC50 for BQ-788-B was not calculable.

Determination of ETA (h) inhibitory effect for BQ-788 and BQ-788-B.FIGS. 5A and 5B demonstrate the determination of ETA (h) inhibitoryeffect for, A) BQ-788 and B) BQ-788-B (i.e., “Compound 1”). Cellularagonist effect was calculated as a % of control response to a knownreference agonist for ETA (h), and cellular antagonist effect wascalculated as a % inhibition of control reference agonist response forETA. Results showing ≥50% inhibition of agonist effect are consideredsignificant while those showing less than 25% inhibition are notconsidered significant. The IC50 for BQ-788 and BQ-788-B was notcalculable (i.e., the dose-response curve shows less than 25% effect atthe highest validated testing concentration).

Determination of ETBR inhibitory effect for specifically deuterated ETRBantagonists. FIG. 6 demonstrates that specifically deuterated ETRBantagonists inhibit melanoma growth and metastasis, and induce apoptosisin melanoma tumor cells. Cellular agonist effect was calculated as a %of control response to a known reference agonist for ETB (h), andcellular antagonist effect was calculated as a % inhibition of controlreference agonist response for ETB. Results showing ≥50% inhibition ofagonist effect are considered significant while those showing less than25% inhibition are not considered significant. The IC50 for anon-deuterated ETRB antagonist was 5.1E08 M and the Kd was 1.3E−08;while the IC50 for specifically deuterated ETRB antagonists were 9.6E−08M and a Kd of 2.5E−08. Surprisingly, in PK studies in vivo, thespecifically deuterated ETRB antagonists demonstrated enhanced biologicactivity relative to the non-deuterated counterpart.

Plasma concentrations of BQ-788 versus BQ-788-B. FIG. 7 illustrates thatBQ-788-B (curve “B”), a deuterated analog of BQ-788, demonstratesenhanced plasma concentrations relative to BQ-788. Briefly, rats (N=4animals per timepoint) were administered either BQ-788 or the deuteratedform, BQ-788-B at a dose of 250 μg/kg via IV infusion. Plasma sampleswere collected at various time points and ET-1 ELISA performed. BQ788and BQ788-B are peptide drugs that are rapidly degraded in plasma andthus drug levels are difficult to detect directly. However, when BQ788binds ETBR, this results in an increase in plasma concentrations ofET-1, the ligand for ETBR. As such, plasma levels of ET-1 are commonlyused as an indirect measure of BQ-788 biologic activity. Significantly,the deuterated compound BQ-788-B demonstrates an enhanced duration andamplitude of response relative to the undeuterated form as exemplifiedby the prolonged peak out to about 3 hours as compared to BQ-788, whichdemonstrates a transient peak at about 30 minutes. The IC50 for BQ-788-Bis 9.6E−08 M (MW=665.37). The IC50 for BQ-788 is 5.6E−08 (MW=663.78).

BQ-788-B in combination with anti-PD1 demonstrates synergistic results.Dual combination of specifically deuterated compounds andimmunotherapeutics (FIG. 8), result in superior efficacy relativecombinations with approved cancer drugs. The syngenic melanoma modelV600E+(BRAF mutated) SM1 tumor model was used in C57BL/6 mice to assessefficacy of deuterated ETRB antagonists in combination withimmunotherapeutics (“B+P”) as compared to a standard treatment,dabrafenib with anti-PD1 (“D+P”). Previous studies have indicated thatV600E+ model demonstrates no efficacy for anti-PD1 as a single agent(and little tumor infiltrating lymphocytes (TILs)). In this study 6-8week old female C57BL/6 mice were inoculated with SM1 tumor fragments(TME* components present). Dosing was initiated when tumors were 150mm3. The general dosing schemes were as follows: dabrafenib (30 mg/kgdaily by oral gavage), immunotherapeutic 10 mg/kg Q4D IP beginning 2days after dabrafenib), deuterated ETRB antagonist (4 μg administeredQOD IV beginning 2 days after dabrafenib). Tumors were measured threetimes per week, and the study was terminated after 21 days of dosing andIHC analysis of tumors was performed. The dual combination of theimmunotherapeutic and the deuterated ETRB antagonist induced tumorshrinkage below baseline. In stark contrast, a standard combination ofdabrafenib and the immunotherapeutic failed to shrink tumors butdemonstrated intermediate tumor growth inhibition. IHC analysis oftumors treated with immunotherapeutics and deuterated ETRB antagonistsrevealed that tumors had been eradicated leaving only residual adiposetissue. In sum, the combination of immunotherapeutic compounds withspecifically deuterated ETRB antagonists as described herein providedsignificant improvement against tumor growth relative to the existingtherapeutic paradigm.

Dual combination BQ-788-B and immunocheckpoint inhibitors eradicatestumors. FIG. 9 demonstrates the results of histological examination ofV600E+ melanoma tumor cells implanted into C57BL/6 mice 21 days aftertreatment as indicated in FIG. 8. The specifically deuterated compoundBQ-788-B and immunocheckpoint inhibitors (e.g. anti-PD1, anti-PD1,anti-CTLA) combination therapy eradicated the tumors in 21 days,promoted robust infiltration by CD8+ lymphocytes (TILs), and tertiarylymphoid organ (TLO) formation. TIL infiltration is exemplified by thedark punctate staining. TLOs are functionally equivalent to lymph nodes,produce tumor-specific T- and B-cells, and induce long lastinganti-tumor immunity.

Intratumoral TLO formation induced by combination therapy includinganti-PD1 and BQ-788-B. FIG. 10 demonstrates the histological examinationof V600E+ melanoma tumor cells implanted into C57BL/6 mice 21 days aftertreatment as indicated in FIG. 8 with BQ-788-B and anti-PD1 combinationtherapy. The staining of CD8+, CD4+ and Treg (FoxP3) lymphocytes (darkpunctate staining) indicates that the combination therapy promotesstrong mobilization of lymphocytes to the tumor, which is associatedwith tumor eradication and positive patient outcomes.

Intratumoral (internal) TLO formation associated with treatment withBQ-788-B. FIG. 11 provides table summaries of the results obtained withcombination therapies (two- and three-part), TLO formation and efficacyfor tumor eradication. The model system tested is as described for FIG.8. The combinations included dabrafenib+anti-PD1 (“D+P”);dabrafenib+anti-PD1+BQ-788-B at 0.6 μg (“D+P+B (0.6 μg)”);dabrafenib+anti-PD1+BQ-788-B at 4.0 μg (“D+P+B (4.0 μg)”);dabrafenib+anti-PD1+BQ-788-B at 100 μg (“D+P+B (100 μg)”); andanti-PD1+BQ-788-B at (4.0 μg) (“P+B (4.0 μg)”). The data indicate that(i) internal TLO formation is associated with tumor eradication; and(ii) the combination of anti-PD1 antibody and BQ-788-B was mostfrequently associated with intratumoral TLO formation and tumorreduction. FIG. 12 presents the efficacy results as a function of tumorvolume (mm3). The inclusion of BQ-788-B with anti-PD1 is synergistic andappears to help restore sensitivity to anti-PD1. The addition ofdabrafenib to anti-PD1/BQ-788-B combination impairs efficacy, possiblydue to dabrafenib's ability to increase Tregs and tumor-associatedmacrophages (TAMs).

BQ-788-B at 0.6 μg in combination with immunocheckpoint inhibitors anddabrafenib promotes diffuse CD8+ TIL staining. FIG. 13 showsdemonstrates the histological examination of V600E+ melanoma tumor cellsimplanted into C57BL/6 mice 21 days after treatment as indicated in FIG.8 with the respective combination therapy. The diffuse distribution ofCD8+ TIL staining (dark punctate staining) appears to be associated withhigher efficacy as compared to those with peripheral distribution ofTILs.

Thus, specifically deuterated forms of BQ-788 as described herein, e.g.,BQ-788-A BQ-788-B, BQ-788-C and others described herein, demonstratesynergistic activity with anti-oncologic agents in a preclinicalmelanoma model in which anti-PD1 lacks any efficacy as a single agent.Tumor reduction or eradication correlates well with intratumoral TLOformation or neogenesis, and diffuse infiltration pattern of TILs ratherthan tumor-peripheral TIL distribution. TLO neogenesis has prognosticimplications and correlates will with increased patient survival. Thedual combination of specifically deuterated ETBR antagonists andanti-oncologic agents is superior to other dual and triple combinationsin terms of (i) anti-tumor efficacy; (ii) low anticipated toxicity(based upon established safety profile of parent compound in humans);and (iii) overall treatment cost (relative to triple therapies). Inaddition, IV administration allows for a 2-3 order of magnitude dosereduction relative to IP or PO administration (e.g. typical doses of200-600 μg BQ788 vs. 0.6-4.0 μg deuterated BQ-788).

Example 3. Treatment of Melanoma in a Human Subject

A human patient suffering melanoma, e.g., malignant melanoma ormetastatic melanoma, is administered compounds or pharmaceuticalcompositions according to a method for treatment disclosed herein. Thetreatment cures the patient or ameliorates the patient's one or moresymptoms such as a sore, spread of pigment from the border of a spotinto surrounding skin, redness or a new swelling beyond the border ofthe mole, change in sensation, such as itchiness, tenderness, or pain,or change in the surface of a mole—scaliness, oozing, bleeding, or theappearance of a lump or bump.

Example 4. Treatment of a Malignant Solid Tumor in a Human Subject

A human patient suffering a malignant solid tumor, e.g., pancreatictumor, ovarian tumor, sarcomas, carcinomas, and lymphomas, isadministered compounds or pharmaceutical compositions according to amethod for treatment disclosed herein. The treatment reduces a tumorvolume or mass, or eradicates the tumor in the patient.

Example 5. Treatment of a Pancreatic Cancer in a Human Subject

A human patient suffering a pancreatic cancer is administered compoundsor pharmaceutical compositions according to a method for treatmentdisclosed herein. The treatment cures the patient or ameliorates thepatient's one or more symptoms such as Jaundice, light-colored stools,dark urine, pain in the upper or middle abdomen and back, weight loss,appetite loss, or fatigue.

Example 6. Treatment of an Ovarian Cancer in a Human Subject

A human patient suffering an ovarian cancer is administered compounds orpharmaceutical compositions according to a method for treatmentdisclosed herein. The treatment cures the patient or ameliorates thepatient's one or more symptoms for example: abdominal bloating,indigestion or nausea, changes in appetite such as a loss of appetite orfeeling full sooner, pressure in the pelvis or lower back, a frequent orurgent need to urinate and/or constipation, changes in bowel movements,increased abdominal girth, tiredness or low energy, or changes inmenstruation.

Example 7. Treatment of Squamous Cell Carcinoma in a Human Subject

A human patient suffering squamous cell carcinoma is administeredcompounds or pharmaceutical compositions according to a method fortreatment disclosed herein. The treatment cures the patient orameliorates the patient's one or more symptoms such as firm red nodule,flat sore with a scaly crust, new sore or raised area on an old scar orulcer, rough scaly path on a lip or inside a mouth, scaly red patches,open sores, or warts or elevated growths with a central depression on orin anus on genitals.

Example 8. Treatment of Glioblastoma in a Human Subject

A human patient suffering glioblastoma is administered compounds orpharmaceutical compositions according to a method for treatmentdisclosed herein. The treatment cures the patient, reduces or eradicatesbrain tumor, or ameliorates the patient's one or more symptoms such asheadache, nausea, vomiting, memory loss, drowsiness, blurred vision,change to personality, mood, or concentration, localized neurologicalproblems, or seizure.

While some embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A compound of Formula (1):

a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,wherein: n is an integer from 0-4; m is an integer from 0-3; X is apositively charged counterion; R₁ and R₃ are independently —H, —D, —CH₃,—CH₂D, —CHD₂, or —CD₃; R_(2a), R_(2b), R₄, R₅, and R₆ are independently—CH₃, —CH₂D, —CHD₂, or —CD₃; and at least one of R₁, R_(2a), R_(2b), andR₃ comprises deuterium.
 2. The compound of claim 1, wherein m is 0, n is0, and R_(2a) and R_(2b) are —CH₂D.
 3. The compound of claim 1, whereinthe compound is of Formula (2):

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein the compound is of Formula (3):

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein the compound is of Formula (4):

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, wherein the compound is of Formula (5):

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein the compound is of Formula (6):


8. The compound of claim 7, wherein n is 0 or
 1. 9. The compound ofclaim 8, wherein n is 1, R₁ is -D; and R_(2a) and R_(2b) are —CH₃. 10.The compound of claim 8, wherein n is 0, R₁ is —H; R_(2a) is —CH₃ andR_(2b) is —CH₂D.
 11. The compound of claim 8, wherein n is 0, R₁ is —H;R_(2a) is —CH₂D and R_(2b) is —CH₃.
 12. The compound of claim 8, whereinn is 0, R₁ is —H; and R_(2a) and R_(2b) are —CH₂D.
 13. The compound ofclaim 8, wherein n is 1, R₁ is -D; and R_(2a) and R_(2b) are —CH₂D. 14.A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a compound of claim 14 or pharmaceuticallyacceptable salt thereof; and a pharmaceutically acceptable excipient,diluent, or carrier.
 16. The pharmaceutical composition of claim 15,comprising dimethyl sulfoxide (DMSO).
 17. The pharmaceutical compositionof claim 15, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 18. A method of treatingcancer in a subject in need thereof, comprising administering to thesubject: a pharmaceutical composition comprising a compound of claim 1,and a pharmaceutical composition comprising an immune checkpointinhibitor.
 19. The method of claim 18, wherein the immune checkpointinhibitor is an anti-PD 1 antibody.